UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma

Abstract KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains...
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Autor*in:	Kaja Kostyrko [verfasserIn] Marta Román [verfasserIn] Alex G. Lee [verfasserIn] David R. Simpson [verfasserIn] Phuong T. Dinh [verfasserIn] Stanley G. Leung [verfasserIn] Kieren D. Marini [verfasserIn] Marcus R. Kelly [verfasserIn] Joshua Broyde [verfasserIn] Andrea Califano [verfasserIn] Peter K. Jackson [verfasserIn] E. Alejandro Sweet-Cordero [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Übergeordnetes Werk:	In: Nature Communications - Nature Portfolio, 2016, 14(2023), 1, Seite 18
Übergeordnetes Werk:	volume:14 ; year:2023 ; number:1 ; pages:18

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1038/s41467-023-39591-2

Katalog-ID:	DOAJ092902529

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allfields	10.1038/s41467-023-39591-2 doi (DE-627)DOAJ092902529 (DE-599)DOAJbfd9eceda508466c9e02d6a2c91e89f7 DE-627 ger DE-627 rakwb eng Kaja Kostyrko verfasserin aut UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention. Science Q Marta Román verfasserin aut Alex G. Lee verfasserin aut David R. Simpson verfasserin aut Phuong T. Dinh verfasserin aut Stanley G. Leung verfasserin aut Kieren D. Marini verfasserin aut Marcus R. Kelly verfasserin aut Joshua Broyde verfasserin aut Andrea Califano verfasserin aut Peter K. Jackson verfasserin aut E. Alejandro Sweet-Cordero verfasserin aut In Nature Communications Nature Portfolio, 2016 14(2023), 1, Seite 18 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:14 year:2023 number:1 pages:18 https://doi.org/10.1038/s41467-023-39591-2 kostenfrei https://doaj.org/article/bfd9eceda508466c9e02d6a2c91e89f7 kostenfrei https://doi.org/10.1038/s41467-023-39591-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023 1 18
spelling	10.1038/s41467-023-39591-2 doi (DE-627)DOAJ092902529 (DE-599)DOAJbfd9eceda508466c9e02d6a2c91e89f7 DE-627 ger DE-627 rakwb eng Kaja Kostyrko verfasserin aut UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention. Science Q Marta Román verfasserin aut Alex G. Lee verfasserin aut David R. Simpson verfasserin aut Phuong T. Dinh verfasserin aut Stanley G. Leung verfasserin aut Kieren D. Marini verfasserin aut Marcus R. Kelly verfasserin aut Joshua Broyde verfasserin aut Andrea Califano verfasserin aut Peter K. Jackson verfasserin aut E. Alejandro Sweet-Cordero verfasserin aut In Nature Communications Nature Portfolio, 2016 14(2023), 1, Seite 18 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:14 year:2023 number:1 pages:18 https://doi.org/10.1038/s41467-023-39591-2 kostenfrei https://doaj.org/article/bfd9eceda508466c9e02d6a2c91e89f7 kostenfrei https://doi.org/10.1038/s41467-023-39591-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023 1 18
allfields_unstemmed	10.1038/s41467-023-39591-2 doi (DE-627)DOAJ092902529 (DE-599)DOAJbfd9eceda508466c9e02d6a2c91e89f7 DE-627 ger DE-627 rakwb eng Kaja Kostyrko verfasserin aut UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention. Science Q Marta Román verfasserin aut Alex G. Lee verfasserin aut David R. Simpson verfasserin aut Phuong T. Dinh verfasserin aut Stanley G. Leung verfasserin aut Kieren D. Marini verfasserin aut Marcus R. Kelly verfasserin aut Joshua Broyde verfasserin aut Andrea Califano verfasserin aut Peter K. Jackson verfasserin aut E. Alejandro Sweet-Cordero verfasserin aut In Nature Communications Nature Portfolio, 2016 14(2023), 1, Seite 18 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:14 year:2023 number:1 pages:18 https://doi.org/10.1038/s41467-023-39591-2 kostenfrei https://doaj.org/article/bfd9eceda508466c9e02d6a2c91e89f7 kostenfrei https://doi.org/10.1038/s41467-023-39591-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023 1 18
allfieldsGer	10.1038/s41467-023-39591-2 doi (DE-627)DOAJ092902529 (DE-599)DOAJbfd9eceda508466c9e02d6a2c91e89f7 DE-627 ger DE-627 rakwb eng Kaja Kostyrko verfasserin aut UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention. Science Q Marta Román verfasserin aut Alex G. Lee verfasserin aut David R. Simpson verfasserin aut Phuong T. Dinh verfasserin aut Stanley G. Leung verfasserin aut Kieren D. Marini verfasserin aut Marcus R. Kelly verfasserin aut Joshua Broyde verfasserin aut Andrea Califano verfasserin aut Peter K. Jackson verfasserin aut E. Alejandro Sweet-Cordero verfasserin aut In Nature Communications Nature Portfolio, 2016 14(2023), 1, Seite 18 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:14 year:2023 number:1 pages:18 https://doi.org/10.1038/s41467-023-39591-2 kostenfrei https://doaj.org/article/bfd9eceda508466c9e02d6a2c91e89f7 kostenfrei https://doi.org/10.1038/s41467-023-39591-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023 1 18
allfieldsSound	10.1038/s41467-023-39591-2 doi (DE-627)DOAJ092902529 (DE-599)DOAJbfd9eceda508466c9e02d6a2c91e89f7 DE-627 ger DE-627 rakwb eng Kaja Kostyrko verfasserin aut UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention. Science Q Marta Román verfasserin aut Alex G. Lee verfasserin aut David R. Simpson verfasserin aut Phuong T. Dinh verfasserin aut Stanley G. Leung verfasserin aut Kieren D. Marini verfasserin aut Marcus R. Kelly verfasserin aut Joshua Broyde verfasserin aut Andrea Califano verfasserin aut Peter K. Jackson verfasserin aut E. Alejandro Sweet-Cordero verfasserin aut In Nature Communications Nature Portfolio, 2016 14(2023), 1, Seite 18 (DE-627)626457688 (DE-600)2553671-0 20411723 nnns volume:14 year:2023 number:1 pages:18 https://doi.org/10.1038/s41467-023-39591-2 kostenfrei https://doaj.org/article/bfd9eceda508466c9e02d6a2c91e89f7 kostenfrei https://doi.org/10.1038/s41467-023-39591-2 kostenfrei https://doaj.org/toc/2041-1723 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_171 GBV_ILN_211 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_2014 GBV_ILN_2110 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 14 2023 1 18
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author	Kaja Kostyrko
spellingShingle	Kaja Kostyrko misc Science misc Q UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma
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topic_title	UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma
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title	UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma
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title_full	UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma
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author_browse	Kaja Kostyrko Marta Román Alex G. Lee David R. Simpson Phuong T. Dinh Stanley G. Leung Kieren D. Marini Marcus R. Kelly Joshua Broyde Andrea Califano Peter K. Jackson E. Alejandro Sweet-Cordero
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title_sort	uhrf1 is a mediator of kras driven oncogenesis in lung adenocarcinoma
title_auth	UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma
abstract	Abstract KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention.
abstractGer	Abstract KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention.
abstract_unstemmed	Abstract KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention.
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title_short	UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma
url	https://doi.org/10.1038/s41467-023-39591-2 https://doaj.org/article/bfd9eceda508466c9e02d6a2c91e89f7 https://doaj.org/toc/2041-1723
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