Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8

Mutation of the p53 gene is the most common genetic alteration in human cancer and contributes to malignant process by enhancing transformed properties of cells and resistance to anticancer therapy. Mutant p53 is often highly expressed in tumor cells at least in part due to its increased half-life....

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Main Authors:	Yan, Wensheng, Liu, Shou, Xu, Enshun, Zhang, Jin, Zhang, Yanhong, Chen, Xiufang, Chen, Xinbin
Format:	Online
Language:	English
Published:	2012
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371110/

id	pubmed-3371110
recordtype	oai_dc
spelling	pubmed-33711102013-07-31 Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8 Yan, Wensheng Liu, Shou Xu, Enshun Zhang, Jin Zhang, Yanhong Chen, Xiufang Chen, Xinbin Article Mutation of the p53 gene is the most common genetic alteration in human cancer and contributes to malignant process by enhancing transformed properties of cells and resistance to anticancer therapy. Mutant p53 is often highly expressed in tumor cells at least in part due to its increased half-life. However, whether mutant p53 expression is regulated by other mechanisms in tumors is unclear. Here, we found that histone deacetylase inhibitors suppress both wild-type and mutant p53 transcription in time- and dose-dependent manners. Consistent with this, the levels of wild-type and mutant p53 proteins are decreased upon treatment with HDAC inhibitors. Importantly, we found that upon knockdown of each class I HDAC, only HDAC8 knockdown leads to decreased expression of wild-type and mutant p53 proteins and transcripts. Conversely, we found that ectopic expression of wild-type but not mutant HDAC8 leads to increased transcription of p53. Furthermore, we found that knockdown of HDAC8 results in reduced expression of HoxA5 and consequently attenuated ability of HoxA5 to activate p53 transcription, which can be rescued by ectopic expression of HoxA5. Due to the fact that HDAC8 is required for expression of both wild-type and mutant p53, we found that targeted disruption of HDAC8 expression remarkably triggers proliferative defect in cells with a mutant, but not wild-type, p53. Together, our data uncover a regulatory mechanism of mutant p53 transcription via HDAC8 and suggest that HDAC inhibitors and especially HDAC8-targeting agents might be explored as an adjuvant for tumors carrying a mutant p53. 2012-03-05 2013-01-31 /pmc/articles/PMC3371110/ /pubmed/22391568 http://dx.doi.org/10.1038/onc.2012.81 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Yan, Wensheng Liu, Shou Xu, Enshun Zhang, Jin Zhang, Yanhong Chen, Xiufang Chen, Xinbin
spellingShingle	Yan, Wensheng Liu, Shou Xu, Enshun Zhang, Jin Zhang, Yanhong Chen, Xiufang Chen, Xinbin Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8
author_facet	Yan, Wensheng Liu, Shou Xu, Enshun Zhang, Jin Zhang, Yanhong Chen, Xiufang Chen, Xinbin
author_sort	Yan, Wensheng
title	Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8
title_short	Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8
title_full	Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8
title_fullStr	Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8
title_full_unstemmed	Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8
title_sort	histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8
description	Mutation of the p53 gene is the most common genetic alteration in human cancer and contributes to malignant process by enhancing transformed properties of cells and resistance to anticancer therapy. Mutant p53 is often highly expressed in tumor cells at least in part due to its increased half-life. However, whether mutant p53 expression is regulated by other mechanisms in tumors is unclear. Here, we found that histone deacetylase inhibitors suppress both wild-type and mutant p53 transcription in time- and dose-dependent manners. Consistent with this, the levels of wild-type and mutant p53 proteins are decreased upon treatment with HDAC inhibitors. Importantly, we found that upon knockdown of each class I HDAC, only HDAC8 knockdown leads to decreased expression of wild-type and mutant p53 proteins and transcripts. Conversely, we found that ectopic expression of wild-type but not mutant HDAC8 leads to increased transcription of p53. Furthermore, we found that knockdown of HDAC8 results in reduced expression of HoxA5 and consequently attenuated ability of HoxA5 to activate p53 transcription, which can be rescued by ectopic expression of HoxA5. Due to the fact that HDAC8 is required for expression of both wild-type and mutant p53, we found that targeted disruption of HDAC8 expression remarkably triggers proliferative defect in cells with a mutant, but not wild-type, p53. Together, our data uncover a regulatory mechanism of mutant p53 transcription via HDAC8 and suggest that HDAC inhibitors and especially HDAC8-targeting agents might be explored as an adjuvant for tumors carrying a mutant p53.
publishDate	2012
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3371110/
_version_	1611535505518755840

Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8

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