Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer

Abstract Background Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, there...
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Autor*in:	Parijat Senapati [verfasserIn] Hiroyuki Kato [verfasserIn] Michael Lee [verfasserIn] Amy Leung [verfasserIn] Christine Thai [verfasserIn] Angelica Sanchez [verfasserIn] Emily J. Gallagher [verfasserIn] Derek LeRoith [verfasserIn] Victoria L. Seewaldt [verfasserIn] David K. Ann [verfasserIn] Dustin E. Schones [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	Insulin Histone acetylation Hyperinsulinemia TNBC Chromatin

Übergeordnetes Werk:	In: Epigenetics & Chromatin - BMC, 2010, 12(2019), 1, Seite 15
Übergeordnetes Werk:	volume:12 ; year:2019 ; number:1 ; pages:15

Links:	Link aufrufen Link aufrufen Link aufrufen Journal toc

DOI / URN:	10.1186/s13072-019-0290-9

Katalog-ID:	DOAJ001293435

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520			\|a Abstract Background Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. Results MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. Conclusions These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.
650		4	\|a Insulin
650		4	\|a Histone acetylation
650		4	\|a Hyperinsulinemia
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allfields	10.1186/s13072-019-0290-9 doi (DE-627)DOAJ001293435 (DE-599)DOAJd7335b0fd4b044189496f088802659ef DE-627 ger DE-627 rakwb eng QH426-470 Parijat Senapati verfasserin aut Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. Results MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. Conclusions These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC. Insulin Histone acetylation Hyperinsulinemia TNBC Chromatin Genetics Hiroyuki Kato verfasserin aut Michael Lee verfasserin aut Amy Leung verfasserin aut Christine Thai verfasserin aut Angelica Sanchez verfasserin aut Emily J. Gallagher verfasserin aut Derek LeRoith verfasserin aut Victoria L. Seewaldt verfasserin aut David K. Ann verfasserin aut Dustin E. Schones verfasserin aut In Epigenetics & Chromatin BMC, 2010 12(2019), 1, Seite 15 (DE-627)584406908 (DE-600)2462129-8 17568935 nnns volume:12 year:2019 number:1 pages:15 https://doi.org/10.1186/s13072-019-0290-9 kostenfrei https://doaj.org/article/d7335b0fd4b044189496f088802659ef kostenfrei http://link.springer.com/article/10.1186/s13072-019-0290-9 kostenfrei https://doaj.org/toc/1756-8935 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_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_2190 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_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2019 1 15
spelling	10.1186/s13072-019-0290-9 doi (DE-627)DOAJ001293435 (DE-599)DOAJd7335b0fd4b044189496f088802659ef DE-627 ger DE-627 rakwb eng QH426-470 Parijat Senapati verfasserin aut Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. Results MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. Conclusions These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC. Insulin Histone acetylation Hyperinsulinemia TNBC Chromatin Genetics Hiroyuki Kato verfasserin aut Michael Lee verfasserin aut Amy Leung verfasserin aut Christine Thai verfasserin aut Angelica Sanchez verfasserin aut Emily J. Gallagher verfasserin aut Derek LeRoith verfasserin aut Victoria L. Seewaldt verfasserin aut David K. Ann verfasserin aut Dustin E. Schones verfasserin aut In Epigenetics & Chromatin BMC, 2010 12(2019), 1, Seite 15 (DE-627)584406908 (DE-600)2462129-8 17568935 nnns volume:12 year:2019 number:1 pages:15 https://doi.org/10.1186/s13072-019-0290-9 kostenfrei https://doaj.org/article/d7335b0fd4b044189496f088802659ef kostenfrei http://link.springer.com/article/10.1186/s13072-019-0290-9 kostenfrei https://doaj.org/toc/1756-8935 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_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_2190 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_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2019 1 15
allfields_unstemmed	10.1186/s13072-019-0290-9 doi (DE-627)DOAJ001293435 (DE-599)DOAJd7335b0fd4b044189496f088802659ef DE-627 ger DE-627 rakwb eng QH426-470 Parijat Senapati verfasserin aut Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. Results MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. Conclusions These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC. Insulin Histone acetylation Hyperinsulinemia TNBC Chromatin Genetics Hiroyuki Kato verfasserin aut Michael Lee verfasserin aut Amy Leung verfasserin aut Christine Thai verfasserin aut Angelica Sanchez verfasserin aut Emily J. Gallagher verfasserin aut Derek LeRoith verfasserin aut Victoria L. Seewaldt verfasserin aut David K. Ann verfasserin aut Dustin E. Schones verfasserin aut In Epigenetics & Chromatin BMC, 2010 12(2019), 1, Seite 15 (DE-627)584406908 (DE-600)2462129-8 17568935 nnns volume:12 year:2019 number:1 pages:15 https://doi.org/10.1186/s13072-019-0290-9 kostenfrei https://doaj.org/article/d7335b0fd4b044189496f088802659ef kostenfrei http://link.springer.com/article/10.1186/s13072-019-0290-9 kostenfrei https://doaj.org/toc/1756-8935 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_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_2190 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_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2019 1 15
allfieldsGer	10.1186/s13072-019-0290-9 doi (DE-627)DOAJ001293435 (DE-599)DOAJd7335b0fd4b044189496f088802659ef DE-627 ger DE-627 rakwb eng QH426-470 Parijat Senapati verfasserin aut Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. Results MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. Conclusions These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC. Insulin Histone acetylation Hyperinsulinemia TNBC Chromatin Genetics Hiroyuki Kato verfasserin aut Michael Lee verfasserin aut Amy Leung verfasserin aut Christine Thai verfasserin aut Angelica Sanchez verfasserin aut Emily J. Gallagher verfasserin aut Derek LeRoith verfasserin aut Victoria L. Seewaldt verfasserin aut David K. Ann verfasserin aut Dustin E. Schones verfasserin aut In Epigenetics & Chromatin BMC, 2010 12(2019), 1, Seite 15 (DE-627)584406908 (DE-600)2462129-8 17568935 nnns volume:12 year:2019 number:1 pages:15 https://doi.org/10.1186/s13072-019-0290-9 kostenfrei https://doaj.org/article/d7335b0fd4b044189496f088802659ef kostenfrei http://link.springer.com/article/10.1186/s13072-019-0290-9 kostenfrei https://doaj.org/toc/1756-8935 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_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_2190 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_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2019 1 15
allfieldsSound	10.1186/s13072-019-0290-9 doi (DE-627)DOAJ001293435 (DE-599)DOAJd7335b0fd4b044189496f088802659ef DE-627 ger DE-627 rakwb eng QH426-470 Parijat Senapati verfasserin aut Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Abstract Background Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. Results MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. Conclusions These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC. Insulin Histone acetylation Hyperinsulinemia TNBC Chromatin Genetics Hiroyuki Kato verfasserin aut Michael Lee verfasserin aut Amy Leung verfasserin aut Christine Thai verfasserin aut Angelica Sanchez verfasserin aut Emily J. Gallagher verfasserin aut Derek LeRoith verfasserin aut Victoria L. Seewaldt verfasserin aut David K. Ann verfasserin aut Dustin E. Schones verfasserin aut In Epigenetics & Chromatin BMC, 2010 12(2019), 1, Seite 15 (DE-627)584406908 (DE-600)2462129-8 17568935 nnns volume:12 year:2019 number:1 pages:15 https://doi.org/10.1186/s13072-019-0290-9 kostenfrei https://doaj.org/article/d7335b0fd4b044189496f088802659ef kostenfrei http://link.springer.com/article/10.1186/s13072-019-0290-9 kostenfrei https://doaj.org/toc/1756-8935 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_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_2190 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_4338 GBV_ILN_4367 GBV_ILN_4700 AR 12 2019 1 15
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authorswithroles_txt_mv	Parijat Senapati @@aut@@ Hiroyuki Kato @@aut@@ Michael Lee @@aut@@ Amy Leung @@aut@@ Christine Thai @@aut@@ Angelica Sanchez @@aut@@ Emily J. Gallagher @@aut@@ Derek LeRoith @@aut@@ Victoria L. Seewaldt @@aut@@ David K. Ann @@aut@@ Dustin E. Schones @@aut@@
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callnumber-first	Q - Science
author	Parijat Senapati
spellingShingle	Parijat Senapati misc QH426-470 misc Insulin misc Histone acetylation misc Hyperinsulinemia misc TNBC misc Chromatin misc Genetics Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer
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topic_title	QH426-470 Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer Insulin Histone acetylation Hyperinsulinemia TNBC Chromatin
topic	misc QH426-470 misc Insulin misc Histone acetylation misc Hyperinsulinemia misc TNBC misc Chromatin misc Genetics
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title	Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer
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title_full	Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer
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title_sort	hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer
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title_auth	Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer
abstract	Abstract Background Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. Results MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. Conclusions These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.
abstractGer	Abstract Background Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. Results MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. Conclusions These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.
abstract_unstemmed	Abstract Background Hyperinsulinemia, the presence of excess insulin relative to glucose in the blood, is considered to be a poor prognostic indicator for patients with triple-negative breast cancer (TNBC). mTOR, a downstream effector of insulin, enhances mitochondrial biogenesis and activity, thereby increasing acetyl-CoA precursors. Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. Results MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. Conclusions These results demonstrate the impact of hyperinsulinemia on altered gene regulation through chromatin and the importance of targeting hyperinsulinemia-induced processes that lead to chromatin dysfunction in TNBC.
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title_short	Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer
url	https://doi.org/10.1186/s13072-019-0290-9 https://doaj.org/article/d7335b0fd4b044189496f088802659ef http://link.springer.com/article/10.1186/s13072-019-0290-9 https://doaj.org/toc/1756-8935
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up_date	2024-07-03T19:34:10.163Z
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Increased acetyl-CoA can, in turn, be utilized by nuclear acetyltransferases for histone acetylation, a critical feature of genome regulation. While signaling pathways downstream of insulin have been established for sometime, the effect of insulin on chromatin remains unclear. We hypothesized that hyperinsulinemia-induced metabolic changes lead to genome-wide changes in histone acetylation in TNBC. Results MDA-MB-231 cells were xenografted into hyperinsulinemic and wild-type mice. Tumors in the hyperinsulinemic mice displayed elevated levels of histone acetylation compared to tumors in normal insulin conditions. We show that insulin treatment in vitro leads to global increase in chromatin-associated histone acetylation, in particular at H3K9, through the PI3K/AKT/mTOR pathway. Genome-wide analyses revealed that most promoter regions have an increase in histone acetylation upon insulin treatment. In addition, insulin induces higher levels of reactive oxygen species and DNA damage foci in cells. 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Hyperinsulinemia promotes aberrant histone acetylation in triple-negative breast cancer

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