Epigenetic therapy combination of UNC0638 and CI-994 suppresses breast cancer via epigenetic remodeling of BIRC5 and GADD45A

Background: There is currently a growing interest in the roles of epigenetic mechanisms in the diagnosis, prognosis, and therapies associated with precision oncology for breast cancer (BC). This study aimed to demonstrate the clinical significance of euchromatic histone lysine methyltransferase 2 (E...

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Autores principales:	Hung-Yu Lin, Hsing-Ju Wu, Si-Yun Chen, Ming-Feng Hou, Chang-Shen Lin, Pei-Yi Chu
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	breast cancer combination therapy epigenetic therapy UNC0638 CI-994 (tacedinaline) Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/a291d1bf11ea48329b277737bc2530f7
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spelling	oai:doaj.org-article:a291d1bf11ea48329b277737bc2530f72021-11-18T04:43:37ZEpigenetic therapy combination of UNC0638 and CI-994 suppresses breast cancer via epigenetic remodeling of BIRC5 and GADD45A0753-332210.1016/j.biopha.2021.112431https://doaj.org/article/a291d1bf11ea48329b277737bc2530f72022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S0753332221012178https://doaj.org/toc/0753-3322Background: There is currently a growing interest in the roles of epigenetic mechanisms in the diagnosis, prognosis, and therapies associated with precision oncology for breast cancer (BC). This study aimed to demonstrate the clinical significance of euchromatic histone lysine methyltransferase 2 (EHMT2), histone deacetylase 1 (HDAC1) and HDAC2 in BC, to evaluate the antitumor effectiveness of a combination of the selective inhibitors UNC0638 and CI-994 (U+C), and to clarify the underlying mechanisms. Methods: Multi-omic analysis was used to study the clinical significance of the biomarkers of interest. The effects of U+C treatment were evaluated by detecting cell viability, cell cycle, apoptosis, and representative gene expressions. RNA-Seq and Gene Set Enrichment Analysis (GSEA) were employed to identify over-represented genes associated with the treatment. Chromatin immunoprecipitation and qPCR (ChIP-qPCR) assay were applied to verify epigenetic profiling on the identified promoters. Results: The significance of elevated expressions of EHMT2, HDAC1, and HDAC2 in tumor tissue and BC basal-like subtype in predicting a poor prognosis was noted. The U+C combined treatment showed an enhanced suppressive effect as compared to single agent treatment, perturbed the cell cycle, induced apoptosis, reduced expressions of the genes representing anti-apoptosis, stemness, drug resistance and basal-like state, while increasing luminal-like state genes. In addition, the combined U+C treatment suppressed xenograft tumor growth. The epigenetic reprogramming of histones was identified in the down-regulated BIRC5 and upregulated GADD45A. Conclusion: These findings demonstrate that selectively targeting EHMT2, HDAC1, and HDAC2 by concurrent U+C treatment suppresses BC tumor progression via epigenetic remodeling of BIRC5 and GADD45A.Hung-Yu LinHsing-Ju WuSi-Yun ChenMing-Feng HouChang-Shen LinPei-Yi ChuElsevierarticlebreast cancercombination therapyepigenetic therapyUNC0638CI-994 (tacedinaline)Therapeutics. PharmacologyRM1-950ENBiomedicine & Pharmacotherapy, Vol 145, Iss , Pp 112431- (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	breast cancer combination therapy epigenetic therapy UNC0638 CI-994 (tacedinaline) Therapeutics. Pharmacology RM1-950
spellingShingle	breast cancer combination therapy epigenetic therapy UNC0638 CI-994 (tacedinaline) Therapeutics. Pharmacology RM1-950 Hung-Yu Lin Hsing-Ju Wu Si-Yun Chen Ming-Feng Hou Chang-Shen Lin Pei-Yi Chu Epigenetic therapy combination of UNC0638 and CI-994 suppresses breast cancer via epigenetic remodeling of BIRC5 and GADD45A
description	Background: There is currently a growing interest in the roles of epigenetic mechanisms in the diagnosis, prognosis, and therapies associated with precision oncology for breast cancer (BC). This study aimed to demonstrate the clinical significance of euchromatic histone lysine methyltransferase 2 (EHMT2), histone deacetylase 1 (HDAC1) and HDAC2 in BC, to evaluate the antitumor effectiveness of a combination of the selective inhibitors UNC0638 and CI-994 (U+C), and to clarify the underlying mechanisms. Methods: Multi-omic analysis was used to study the clinical significance of the biomarkers of interest. The effects of U+C treatment were evaluated by detecting cell viability, cell cycle, apoptosis, and representative gene expressions. RNA-Seq and Gene Set Enrichment Analysis (GSEA) were employed to identify over-represented genes associated with the treatment. Chromatin immunoprecipitation and qPCR (ChIP-qPCR) assay were applied to verify epigenetic profiling on the identified promoters. Results: The significance of elevated expressions of EHMT2, HDAC1, and HDAC2 in tumor tissue and BC basal-like subtype in predicting a poor prognosis was noted. The U+C combined treatment showed an enhanced suppressive effect as compared to single agent treatment, perturbed the cell cycle, induced apoptosis, reduced expressions of the genes representing anti-apoptosis, stemness, drug resistance and basal-like state, while increasing luminal-like state genes. In addition, the combined U+C treatment suppressed xenograft tumor growth. The epigenetic reprogramming of histones was identified in the down-regulated BIRC5 and upregulated GADD45A. Conclusion: These findings demonstrate that selectively targeting EHMT2, HDAC1, and HDAC2 by concurrent U+C treatment suppresses BC tumor progression via epigenetic remodeling of BIRC5 and GADD45A.
format	article
author	Hung-Yu Lin Hsing-Ju Wu Si-Yun Chen Ming-Feng Hou Chang-Shen Lin Pei-Yi Chu
author_facet	Hung-Yu Lin Hsing-Ju Wu Si-Yun Chen Ming-Feng Hou Chang-Shen Lin Pei-Yi Chu
author_sort	Hung-Yu Lin
title	Epigenetic therapy combination of UNC0638 and CI-994 suppresses breast cancer via epigenetic remodeling of BIRC5 and GADD45A
title_short	Epigenetic therapy combination of UNC0638 and CI-994 suppresses breast cancer via epigenetic remodeling of BIRC5 and GADD45A
title_full	Epigenetic therapy combination of UNC0638 and CI-994 suppresses breast cancer via epigenetic remodeling of BIRC5 and GADD45A
title_fullStr	Epigenetic therapy combination of UNC0638 and CI-994 suppresses breast cancer via epigenetic remodeling of BIRC5 and GADD45A
title_full_unstemmed	Epigenetic therapy combination of UNC0638 and CI-994 suppresses breast cancer via epigenetic remodeling of BIRC5 and GADD45A
title_sort	epigenetic therapy combination of unc0638 and ci-994 suppresses breast cancer via epigenetic remodeling of birc5 and gadd45a
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/a291d1bf11ea48329b277737bc2530f7
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Epigenetic therapy combination of UNC0638 and CI-994 suppresses breast cancer via epigenetic remodeling of BIRC5 and GADD45A

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