RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy
Abstract N6‐methyladenosine ($ m^{6} $A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METT...
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Gespeichert in:
| Autor*in: |
Lin, Ziyou [verfasserIn] Niu, Yi [verfasserIn] Wan, Arabella [verfasserIn] Chen, Dongshi [verfasserIn] Liang, Heng [verfasserIn] Chen, Xijun [verfasserIn] Sun, Lei [verfasserIn] Zhan, Siyue [verfasserIn] Chen, Liutao [verfasserIn] Cheng, Chao [verfasserIn] Zhang, Xiaolei [verfasserIn] Bu, Xianzhang [verfasserIn] He, Weiling [verfasserIn] Wan, Guohui [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2020 |
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| Schlagwörter: |
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| Anmerkung: |
© The Author(s) 2020 |
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| Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 39(2020), 12 vom: 05. Mai |
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| Übergeordnetes Werk: |
volume:39 ; year:2020 ; number:12 ; day:05 ; month:05 |
| Links: |
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| DOI / URN: |
10.15252/embj.2019103181 |
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| Katalog-ID: |
SPR058017992 |
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| 100 | 1 | |a Lin, Ziyou |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy |
| 264 | 1 | |c 2020 | |
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| 520 | |a Abstract N6‐methyladenosine ($ m^{6} $A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary $ m^{6} $A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy‐associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with $ m^{6} $A modification of the FOXO3 mRNA 3′‐untranslated region increasing its stability through a YTHDF1‐dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores $ m^{6} $A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated $ m^{6} $A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of $ m^{6} $A modification in the resistance of HCC to sorafenib therapy. | ||
| 520 | |a Synopsis METTL3 depletion in the hypoxic tumor microenvironment promotes sorafenib resistance, tumor progression and induction of autophagy. Stabilization of FOXO3 mRNA through METTL3‐mediated m6A modification is critical to prevent induction of autophagy and resistance. METTL3, a primary $ m^{6} $A methyltransferase, is downregulated in sorafenib‐resistant hepatocellular carcinoma (HCC).Depletion of METTL3 enhances sorafenib resistance in HCC under intratumoral environment.FOXO3 is a critical target of METTL3 during sorafenib resistance.m6A modification of FOXO3 promotes mRNA stability in an YTHDF1‐dependent manner. | ||
| 520 | |a Graphical Abstract Stabilization of FOXO3 mRNA by YTHDF1 is impaired in hypoxic sorafenib‐resistant hepatocellular carcinoma due to downregulation of the RNA methyltransferase METLL3. | ||
| 650 | 4 | |a autophagy |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a FOXO3 |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a hypoxia |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a METTL3 |7 (dpeaa)DE-He213 | |
| 650 | 4 | |a N6‐methyladenosine |7 (dpeaa)DE-He213 | |
| 700 | 1 | |a Niu, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Arabella |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Dongshi |e verfasserin |4 aut | |
| 700 | 1 | |a Liang, Heng |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Xijun |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Zhan, Siyue |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Liutao |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Chao |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Xiaolei |e verfasserin |4 aut | |
| 700 | 1 | |a Bu, Xianzhang |e verfasserin |4 aut | |
| 700 | 1 | |a He, Weiling |e verfasserin |4 aut | |
| 700 | 1 | |a Wan, Guohui |e verfasserin |0 (orcid)0000-0001-5170-7282 |4 aut | |
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10.15252/embj.2019103181 doi (DE-627)SPR058017992 (SPR)embj.2019103181-e DE-627 ger DE-627 rakwb eng Lin, Ziyou verfasserin aut RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract N6‐methyladenosine ($ m^{6} $A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary $ m^{6} $A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy‐associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with $ m^{6} $A modification of the FOXO3 mRNA 3′‐untranslated region increasing its stability through a YTHDF1‐dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores $ m^{6} $A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated $ m^{6} $A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of $ m^{6} $A modification in the resistance of HCC to sorafenib therapy. Synopsis METTL3 depletion in the hypoxic tumor microenvironment promotes sorafenib resistance, tumor progression and induction of autophagy. Stabilization of FOXO3 mRNA through METTL3‐mediated m6A modification is critical to prevent induction of autophagy and resistance. METTL3, a primary $ m^{6} $A methyltransferase, is downregulated in sorafenib‐resistant hepatocellular carcinoma (HCC).Depletion of METTL3 enhances sorafenib resistance in HCC under intratumoral environment.FOXO3 is a critical target of METTL3 during sorafenib resistance.m6A modification of FOXO3 promotes mRNA stability in an YTHDF1‐dependent manner. Graphical Abstract Stabilization of FOXO3 mRNA by YTHDF1 is impaired in hypoxic sorafenib‐resistant hepatocellular carcinoma due to downregulation of the RNA methyltransferase METLL3. autophagy (dpeaa)DE-He213 FOXO3 (dpeaa)DE-He213 hypoxia (dpeaa)DE-He213 METTL3 (dpeaa)DE-He213 N6‐methyladenosine (dpeaa)DE-He213 Niu, Yi verfasserin aut Wan, Arabella verfasserin aut Chen, Dongshi verfasserin aut Liang, Heng verfasserin aut Chen, Xijun verfasserin aut Sun, Lei verfasserin aut Zhan, Siyue verfasserin aut Chen, Liutao verfasserin aut Cheng, Chao verfasserin aut Zhang, Xiaolei verfasserin aut Bu, Xianzhang verfasserin aut He, Weiling verfasserin aut Wan, Guohui verfasserin (orcid)0000-0001-5170-7282 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 12 vom: 05. Mai (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:12 day:05 month:05 https://dx.doi.org/10.15252/embj.2019103181 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 12 05 05 |
| spelling |
10.15252/embj.2019103181 doi (DE-627)SPR058017992 (SPR)embj.2019103181-e DE-627 ger DE-627 rakwb eng Lin, Ziyou verfasserin aut RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract N6‐methyladenosine ($ m^{6} $A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary $ m^{6} $A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy‐associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with $ m^{6} $A modification of the FOXO3 mRNA 3′‐untranslated region increasing its stability through a YTHDF1‐dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores $ m^{6} $A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated $ m^{6} $A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of $ m^{6} $A modification in the resistance of HCC to sorafenib therapy. Synopsis METTL3 depletion in the hypoxic tumor microenvironment promotes sorafenib resistance, tumor progression and induction of autophagy. Stabilization of FOXO3 mRNA through METTL3‐mediated m6A modification is critical to prevent induction of autophagy and resistance. METTL3, a primary $ m^{6} $A methyltransferase, is downregulated in sorafenib‐resistant hepatocellular carcinoma (HCC).Depletion of METTL3 enhances sorafenib resistance in HCC under intratumoral environment.FOXO3 is a critical target of METTL3 during sorafenib resistance.m6A modification of FOXO3 promotes mRNA stability in an YTHDF1‐dependent manner. Graphical Abstract Stabilization of FOXO3 mRNA by YTHDF1 is impaired in hypoxic sorafenib‐resistant hepatocellular carcinoma due to downregulation of the RNA methyltransferase METLL3. autophagy (dpeaa)DE-He213 FOXO3 (dpeaa)DE-He213 hypoxia (dpeaa)DE-He213 METTL3 (dpeaa)DE-He213 N6‐methyladenosine (dpeaa)DE-He213 Niu, Yi verfasserin aut Wan, Arabella verfasserin aut Chen, Dongshi verfasserin aut Liang, Heng verfasserin aut Chen, Xijun verfasserin aut Sun, Lei verfasserin aut Zhan, Siyue verfasserin aut Chen, Liutao verfasserin aut Cheng, Chao verfasserin aut Zhang, Xiaolei verfasserin aut Bu, Xianzhang verfasserin aut He, Weiling verfasserin aut Wan, Guohui verfasserin (orcid)0000-0001-5170-7282 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 12 vom: 05. Mai (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:12 day:05 month:05 https://dx.doi.org/10.15252/embj.2019103181 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 12 05 05 |
| allfields_unstemmed |
10.15252/embj.2019103181 doi (DE-627)SPR058017992 (SPR)embj.2019103181-e DE-627 ger DE-627 rakwb eng Lin, Ziyou verfasserin aut RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract N6‐methyladenosine ($ m^{6} $A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary $ m^{6} $A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy‐associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with $ m^{6} $A modification of the FOXO3 mRNA 3′‐untranslated region increasing its stability through a YTHDF1‐dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores $ m^{6} $A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated $ m^{6} $A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of $ m^{6} $A modification in the resistance of HCC to sorafenib therapy. Synopsis METTL3 depletion in the hypoxic tumor microenvironment promotes sorafenib resistance, tumor progression and induction of autophagy. Stabilization of FOXO3 mRNA through METTL3‐mediated m6A modification is critical to prevent induction of autophagy and resistance. METTL3, a primary $ m^{6} $A methyltransferase, is downregulated in sorafenib‐resistant hepatocellular carcinoma (HCC).Depletion of METTL3 enhances sorafenib resistance in HCC under intratumoral environment.FOXO3 is a critical target of METTL3 during sorafenib resistance.m6A modification of FOXO3 promotes mRNA stability in an YTHDF1‐dependent manner. Graphical Abstract Stabilization of FOXO3 mRNA by YTHDF1 is impaired in hypoxic sorafenib‐resistant hepatocellular carcinoma due to downregulation of the RNA methyltransferase METLL3. autophagy (dpeaa)DE-He213 FOXO3 (dpeaa)DE-He213 hypoxia (dpeaa)DE-He213 METTL3 (dpeaa)DE-He213 N6‐methyladenosine (dpeaa)DE-He213 Niu, Yi verfasserin aut Wan, Arabella verfasserin aut Chen, Dongshi verfasserin aut Liang, Heng verfasserin aut Chen, Xijun verfasserin aut Sun, Lei verfasserin aut Zhan, Siyue verfasserin aut Chen, Liutao verfasserin aut Cheng, Chao verfasserin aut Zhang, Xiaolei verfasserin aut Bu, Xianzhang verfasserin aut He, Weiling verfasserin aut Wan, Guohui verfasserin (orcid)0000-0001-5170-7282 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 12 vom: 05. Mai (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:12 day:05 month:05 https://dx.doi.org/10.15252/embj.2019103181 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 12 05 05 |
| allfieldsGer |
10.15252/embj.2019103181 doi (DE-627)SPR058017992 (SPR)embj.2019103181-e DE-627 ger DE-627 rakwb eng Lin, Ziyou verfasserin aut RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract N6‐methyladenosine ($ m^{6} $A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary $ m^{6} $A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy‐associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with $ m^{6} $A modification of the FOXO3 mRNA 3′‐untranslated region increasing its stability through a YTHDF1‐dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores $ m^{6} $A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated $ m^{6} $A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of $ m^{6} $A modification in the resistance of HCC to sorafenib therapy. Synopsis METTL3 depletion in the hypoxic tumor microenvironment promotes sorafenib resistance, tumor progression and induction of autophagy. Stabilization of FOXO3 mRNA through METTL3‐mediated m6A modification is critical to prevent induction of autophagy and resistance. METTL3, a primary $ m^{6} $A methyltransferase, is downregulated in sorafenib‐resistant hepatocellular carcinoma (HCC).Depletion of METTL3 enhances sorafenib resistance in HCC under intratumoral environment.FOXO3 is a critical target of METTL3 during sorafenib resistance.m6A modification of FOXO3 promotes mRNA stability in an YTHDF1‐dependent manner. Graphical Abstract Stabilization of FOXO3 mRNA by YTHDF1 is impaired in hypoxic sorafenib‐resistant hepatocellular carcinoma due to downregulation of the RNA methyltransferase METLL3. autophagy (dpeaa)DE-He213 FOXO3 (dpeaa)DE-He213 hypoxia (dpeaa)DE-He213 METTL3 (dpeaa)DE-He213 N6‐methyladenosine (dpeaa)DE-He213 Niu, Yi verfasserin aut Wan, Arabella verfasserin aut Chen, Dongshi verfasserin aut Liang, Heng verfasserin aut Chen, Xijun verfasserin aut Sun, Lei verfasserin aut Zhan, Siyue verfasserin aut Chen, Liutao verfasserin aut Cheng, Chao verfasserin aut Zhang, Xiaolei verfasserin aut Bu, Xianzhang verfasserin aut He, Weiling verfasserin aut Wan, Guohui verfasserin (orcid)0000-0001-5170-7282 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 12 vom: 05. Mai (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:12 day:05 month:05 https://dx.doi.org/10.15252/embj.2019103181 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 12 05 05 |
| allfieldsSound |
10.15252/embj.2019103181 doi (DE-627)SPR058017992 (SPR)embj.2019103181-e DE-627 ger DE-627 rakwb eng Lin, Ziyou verfasserin aut RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy 2020 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2020 Abstract N6‐methyladenosine ($ m^{6} $A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary $ m^{6} $A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy‐associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with $ m^{6} $A modification of the FOXO3 mRNA 3′‐untranslated region increasing its stability through a YTHDF1‐dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores $ m^{6} $A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated $ m^{6} $A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of $ m^{6} $A modification in the resistance of HCC to sorafenib therapy. Synopsis METTL3 depletion in the hypoxic tumor microenvironment promotes sorafenib resistance, tumor progression and induction of autophagy. Stabilization of FOXO3 mRNA through METTL3‐mediated m6A modification is critical to prevent induction of autophagy and resistance. METTL3, a primary $ m^{6} $A methyltransferase, is downregulated in sorafenib‐resistant hepatocellular carcinoma (HCC).Depletion of METTL3 enhances sorafenib resistance in HCC under intratumoral environment.FOXO3 is a critical target of METTL3 during sorafenib resistance.m6A modification of FOXO3 promotes mRNA stability in an YTHDF1‐dependent manner. Graphical Abstract Stabilization of FOXO3 mRNA by YTHDF1 is impaired in hypoxic sorafenib‐resistant hepatocellular carcinoma due to downregulation of the RNA methyltransferase METLL3. autophagy (dpeaa)DE-He213 FOXO3 (dpeaa)DE-He213 hypoxia (dpeaa)DE-He213 METTL3 (dpeaa)DE-He213 N6‐methyladenosine (dpeaa)DE-He213 Niu, Yi verfasserin aut Wan, Arabella verfasserin aut Chen, Dongshi verfasserin aut Liang, Heng verfasserin aut Chen, Xijun verfasserin aut Sun, Lei verfasserin aut Zhan, Siyue verfasserin aut Chen, Liutao verfasserin aut Cheng, Chao verfasserin aut Zhang, Xiaolei verfasserin aut Bu, Xianzhang verfasserin aut He, Weiling verfasserin aut Wan, Guohui verfasserin (orcid)0000-0001-5170-7282 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 39(2020), 12 vom: 05. Mai (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:39 year:2020 number:12 day:05 month:05 https://dx.doi.org/10.15252/embj.2019103181 X:SPRINGER Resolving-System kostenfrei Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 39 2020 12 05 05 |
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Enthalten in The EMBO Journal 39(2020), 12 vom: 05. Mai volume:39 year:2020 number:12 day:05 month:05 |
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Enthalten in The EMBO Journal 39(2020), 12 vom: 05. Mai volume:39 year:2020 number:12 day:05 month:05 |
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Lin, Ziyou @@aut@@ Niu, Yi @@aut@@ Wan, Arabella @@aut@@ Chen, Dongshi @@aut@@ Liang, Heng @@aut@@ Chen, Xijun @@aut@@ Sun, Lei @@aut@@ Zhan, Siyue @@aut@@ Chen, Liutao @@aut@@ Cheng, Chao @@aut@@ Zhang, Xiaolei @@aut@@ Bu, Xianzhang @@aut@@ He, Weiling @@aut@@ Wan, Guohui @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058017992</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241024065145.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241024s2020 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/embj.2019103181</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058017992</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)embj.2019103181-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Lin, Ziyou</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2020</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Author(s) 2020</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract N6‐methyladenosine ($ m^{6} $A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary $ m^{6} $A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy‐associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with $ m^{6} $A modification of the FOXO3 mRNA 3′‐untranslated region increasing its stability through a YTHDF1‐dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores $ m^{6} $A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated $ m^{6} $A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of $ m^{6} $A modification in the resistance of HCC to sorafenib therapy.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis METTL3 depletion in the hypoxic tumor microenvironment promotes sorafenib resistance, tumor progression and induction of autophagy. Stabilization of FOXO3 mRNA through METTL3‐mediated m6A modification is critical to prevent induction of autophagy and resistance. METTL3, a primary $ m^{6} $A methyltransferase, is downregulated in sorafenib‐resistant hepatocellular carcinoma (HCC).Depletion of METTL3 enhances sorafenib resistance in HCC under intratumoral environment.FOXO3 is a critical target of METTL3 during sorafenib resistance.m6A modification of FOXO3 promotes mRNA stability in an YTHDF1‐dependent manner.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract Stabilization of FOXO3 mRNA by YTHDF1 is impaired in hypoxic sorafenib‐resistant hepatocellular carcinoma due to downregulation of the RNA methyltransferase METLL3.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">autophagy</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">FOXO3</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">hypoxia</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">METTL3</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">N6‐methyladenosine</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Niu, Yi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wan, Arabella</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Chen, Dongshi</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Liang, Heng</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Chen, Xijun</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Sun, Lei</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zhan, Siyue</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Chen, Liutao</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Cheng, Chao</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Zhang, Xiaolei</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Bu, Xianzhang</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">He, Weiling</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Wan, Guohui</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0001-5170-7282</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">The EMBO Journal</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">39(2020), 12 vom: 05. 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|
| author |
Lin, Ziyou |
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Lin, Ziyou misc autophagy misc FOXO3 misc hypoxia misc METTL3 misc N6‐methyladenosine RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy |
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1460-2075 |
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RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy autophagy (dpeaa)DE-He213 FOXO3 (dpeaa)DE-He213 hypoxia (dpeaa)DE-He213 METTL3 (dpeaa)DE-He213 N6‐methyladenosine (dpeaa)DE-He213 |
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misc autophagy misc FOXO3 misc hypoxia misc METTL3 misc N6‐methyladenosine |
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misc autophagy misc FOXO3 misc hypoxia misc METTL3 misc N6‐methyladenosine |
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misc autophagy misc FOXO3 misc hypoxia misc METTL3 misc N6‐methyladenosine |
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Elektronische Aufsätze Aufsätze Elektronische Ressource |
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RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy |
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RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy |
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Lin, Ziyou Niu, Yi Wan, Arabella Chen, Dongshi Liang, Heng Chen, Xijun Sun, Lei Zhan, Siyue Chen, Liutao Cheng, Chao Zhang, Xiaolei Bu, Xianzhang He, Weiling Wan, Guohui |
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Elektronische Aufsätze |
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rna $ m^{6} $a methylation regulates sorafenib resistance in liver cancer through foxo3‐mediated autophagy |
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RNA $ m^{6} $A methylation regulates sorafenib resistance in liver cancer through FOXO3‐mediated autophagy |
| abstract |
Abstract N6‐methyladenosine ($ m^{6} $A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary $ m^{6} $A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy‐associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with $ m^{6} $A modification of the FOXO3 mRNA 3′‐untranslated region increasing its stability through a YTHDF1‐dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores $ m^{6} $A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated $ m^{6} $A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of $ m^{6} $A modification in the resistance of HCC to sorafenib therapy. Synopsis METTL3 depletion in the hypoxic tumor microenvironment promotes sorafenib resistance, tumor progression and induction of autophagy. Stabilization of FOXO3 mRNA through METTL3‐mediated m6A modification is critical to prevent induction of autophagy and resistance. METTL3, a primary $ m^{6} $A methyltransferase, is downregulated in sorafenib‐resistant hepatocellular carcinoma (HCC).Depletion of METTL3 enhances sorafenib resistance in HCC under intratumoral environment.FOXO3 is a critical target of METTL3 during sorafenib resistance.m6A modification of FOXO3 promotes mRNA stability in an YTHDF1‐dependent manner. Graphical Abstract Stabilization of FOXO3 mRNA by YTHDF1 is impaired in hypoxic sorafenib‐resistant hepatocellular carcinoma due to downregulation of the RNA methyltransferase METLL3. © The Author(s) 2020 |
| abstractGer |
Abstract N6‐methyladenosine ($ m^{6} $A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary $ m^{6} $A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy‐associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with $ m^{6} $A modification of the FOXO3 mRNA 3′‐untranslated region increasing its stability through a YTHDF1‐dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores $ m^{6} $A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated $ m^{6} $A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of $ m^{6} $A modification in the resistance of HCC to sorafenib therapy. Synopsis METTL3 depletion in the hypoxic tumor microenvironment promotes sorafenib resistance, tumor progression and induction of autophagy. Stabilization of FOXO3 mRNA through METTL3‐mediated m6A modification is critical to prevent induction of autophagy and resistance. METTL3, a primary $ m^{6} $A methyltransferase, is downregulated in sorafenib‐resistant hepatocellular carcinoma (HCC).Depletion of METTL3 enhances sorafenib resistance in HCC under intratumoral environment.FOXO3 is a critical target of METTL3 during sorafenib resistance.m6A modification of FOXO3 promotes mRNA stability in an YTHDF1‐dependent manner. Graphical Abstract Stabilization of FOXO3 mRNA by YTHDF1 is impaired in hypoxic sorafenib‐resistant hepatocellular carcinoma due to downregulation of the RNA methyltransferase METLL3. © The Author(s) 2020 |
| abstract_unstemmed |
Abstract N6‐methyladenosine ($ m^{6} $A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary $ m^{6} $A methyltransferase, is significantly down‐regulated in human sorafenib‐resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy‐associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with $ m^{6} $A modification of the FOXO3 mRNA 3′‐untranslated region increasing its stability through a YTHDF1‐dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores $ m^{6} $A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated $ m^{6} $A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of $ m^{6} $A modification in the resistance of HCC to sorafenib therapy. Synopsis METTL3 depletion in the hypoxic tumor microenvironment promotes sorafenib resistance, tumor progression and induction of autophagy. Stabilization of FOXO3 mRNA through METTL3‐mediated m6A modification is critical to prevent induction of autophagy and resistance. METTL3, a primary $ m^{6} $A methyltransferase, is downregulated in sorafenib‐resistant hepatocellular carcinoma (HCC).Depletion of METTL3 enhances sorafenib resistance in HCC under intratumoral environment.FOXO3 is a critical target of METTL3 during sorafenib resistance.m6A modification of FOXO3 promotes mRNA stability in an YTHDF1‐dependent manner. Graphical Abstract Stabilization of FOXO3 mRNA by YTHDF1 is impaired in hypoxic sorafenib‐resistant hepatocellular carcinoma due to downregulation of the RNA methyltransferase METLL3. © The Author(s) 2020 |
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| score |
7.4002895 |