C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer

Abstract The activity of histone acetyltransferases (HATs) plays a central role in an epigenetic modification in cooperation with HDACs (histone deacetyl transferases). It is likely that malfunction of this enzymatic machinery controlling epigenetic modification is relevant to carcinogenesis and tum...

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Autores principales:	Hiroaki Ono, Tomotaka Kato, Yoshiki Murase, Yutaro Nakamura, Yoshiya Ishikawa, Shuichi Watanabe, Keiichi Akahoshi, Toshiro Ogura, Kosuke Ogawa, Daisuke Ban, Atsushi Kudo, Yoshimitsu Akiyama, Shinji Tanaka, Hiromichi Ito, Minoru Tanabe
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ec83439cf09a4bad9247afe1778a20c3
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spelling	oai:doaj.org-article:ec83439cf09a4bad9247afe1778a20c32021-12-02T16:50:27ZC646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer10.1038/s41598-021-89530-82045-2322https://doaj.org/article/ec83439cf09a4bad9247afe1778a20c32021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-89530-8https://doaj.org/toc/2045-2322Abstract The activity of histone acetyltransferases (HATs) plays a central role in an epigenetic modification in cooperation with HDACs (histone deacetyl transferases). It is likely that malfunction of this enzymatic machinery controlling epigenetic modification is relevant to carcinogenesis and tumor progression. However, in pancreatic cancer, the clinical relevance of HAT activity and histone acetylation has remained unclear. We identified that H3 acetylation was expressed in all pancreatic cancer patients, indicating that H3 acetylation may be essential in pancreatic cancer cells. We also found that the HAT inhibitor C646 augmented anti-tumor effects in vitro by inhibiting cell proliferation and cell cycle progression concomitantly with suppression of acetylated H3K9 and H3K27 expression. C646 or p300 and CBP (CREB-binding protein)-specific siRNA treatment inhibited the transcription of the G2/M cell cycle regulatory proteins cyclin B1 and CDK1 (cyclin-dependent kinase 1). C646 treatment also inhibited tumor growth in vivo in a xenograft mouse model. C646 could be an effective therapeutic agent for pancreatic cancer. The epigenetic status of pancreatic cancers based on their level of histone H3 acetylation may influence patient survival. Epigenetic stratification according to H3K27 acetylation could be useful for predicting disease prognosis as well as the therapeutic efficacy of C646 in pancreatic cancer.Hiroaki OnoTomotaka KatoYoshiki MuraseYutaro NakamuraYoshiya IshikawaShuichi WatanabeKeiichi AkahoshiToshiro OguraKosuke OgawaDaisuke BanAtsushi KudoYoshimitsu AkiyamaShinji TanakaHiromichi ItoMinoru TanabeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Hiroaki Ono Tomotaka Kato Yoshiki Murase Yutaro Nakamura Yoshiya Ishikawa Shuichi Watanabe Keiichi Akahoshi Toshiro Ogura Kosuke Ogawa Daisuke Ban Atsushi Kudo Yoshimitsu Akiyama Shinji Tanaka Hiromichi Ito Minoru Tanabe C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer
description	Abstract The activity of histone acetyltransferases (HATs) plays a central role in an epigenetic modification in cooperation with HDACs (histone deacetyl transferases). It is likely that malfunction of this enzymatic machinery controlling epigenetic modification is relevant to carcinogenesis and tumor progression. However, in pancreatic cancer, the clinical relevance of HAT activity and histone acetylation has remained unclear. We identified that H3 acetylation was expressed in all pancreatic cancer patients, indicating that H3 acetylation may be essential in pancreatic cancer cells. We also found that the HAT inhibitor C646 augmented anti-tumor effects in vitro by inhibiting cell proliferation and cell cycle progression concomitantly with suppression of acetylated H3K9 and H3K27 expression. C646 or p300 and CBP (CREB-binding protein)-specific siRNA treatment inhibited the transcription of the G2/M cell cycle regulatory proteins cyclin B1 and CDK1 (cyclin-dependent kinase 1). C646 treatment also inhibited tumor growth in vivo in a xenograft mouse model. C646 could be an effective therapeutic agent for pancreatic cancer. The epigenetic status of pancreatic cancers based on their level of histone H3 acetylation may influence patient survival. Epigenetic stratification according to H3K27 acetylation could be useful for predicting disease prognosis as well as the therapeutic efficacy of C646 in pancreatic cancer.
format	article
author	Hiroaki Ono Tomotaka Kato Yoshiki Murase Yutaro Nakamura Yoshiya Ishikawa Shuichi Watanabe Keiichi Akahoshi Toshiro Ogura Kosuke Ogawa Daisuke Ban Atsushi Kudo Yoshimitsu Akiyama Shinji Tanaka Hiromichi Ito Minoru Tanabe
author_facet	Hiroaki Ono Tomotaka Kato Yoshiki Murase Yutaro Nakamura Yoshiya Ishikawa Shuichi Watanabe Keiichi Akahoshi Toshiro Ogura Kosuke Ogawa Daisuke Ban Atsushi Kudo Yoshimitsu Akiyama Shinji Tanaka Hiromichi Ito Minoru Tanabe
author_sort	Hiroaki Ono
title	C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer
title_short	C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer
title_full	C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer
title_fullStr	C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer
title_full_unstemmed	C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer
title_sort	c646 inhibits g2/m cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ec83439cf09a4bad9247afe1778a20c3
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C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer

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