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Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence

Hepatocyte nuclear factor 4α (HNF4α, NR2A1) is a highly conserved member of the nuclear receptor superfamily. Recent advances reveal that it is a key transcriptional regulator of genes, broadly involved in xenobiotic and drug metabolism and also cancers of gastrointestinal tract. However, the exact...

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Autores principales: Wang, Zhu, Li, Youjia, Wu, Dinglan, Yu, Shan, Wang, Yuliang, Leung Chan, Franky
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018660/
https://www.ncbi.nlm.nih.gov/pubmed/31695151
http://dx.doi.org/10.1038/s41388-019-1080-3
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author Wang, Zhu
Li, Youjia
Wu, Dinglan
Yu, Shan
Wang, Yuliang
Leung Chan, Franky
author_facet Wang, Zhu
Li, Youjia
Wu, Dinglan
Yu, Shan
Wang, Yuliang
Leung Chan, Franky
author_sort Wang, Zhu
collection PubMed
description Hepatocyte nuclear factor 4α (HNF4α, NR2A1) is a highly conserved member of the nuclear receptor superfamily. Recent advances reveal that it is a key transcriptional regulator of genes, broadly involved in xenobiotic and drug metabolism and also cancers of gastrointestinal tract. However, the exact functional roles of HNF4α in prostate cancer progression are still not fully understood. In this study, we determined the functional significance of HNF4α in prostate cancer. Our results showed that HNF4α exhibited a reduced expression pattern in clinical prostate cancer tissues, prostate cancer cell lines and xenograft model of castration-relapse prostate cancer. Stable HNF4α knockdown not only could promote cell proliferation and suppress doxorubicin (Dox)-induced cellular senescence in prostate cancer cells, but also confer resistance to paclitaxel treatment and enhance colony formation capacity and in vivo tumorigenicity of prostate cancer cells. On the contrary, ectopic overexpression of HNF4α could significantly inhibit the cell proliferation of prostate cancer cells, induce cell-cycle arrest at G(2)/M phase and trigger the cellular senescence in prostate cancer cells by activation of p21 signal pathway in a p53-independent manner via its direct transactivation of CDKN1A. Together, our results show that HNF4α performs a tumor suppressor function in prostate cancer via a mechanism of p21-driven cellular senescence.
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spelling pubmed-70186602020-02-18 Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence Wang, Zhu Li, Youjia Wu, Dinglan Yu, Shan Wang, Yuliang Leung Chan, Franky Oncogene Article Hepatocyte nuclear factor 4α (HNF4α, NR2A1) is a highly conserved member of the nuclear receptor superfamily. Recent advances reveal that it is a key transcriptional regulator of genes, broadly involved in xenobiotic and drug metabolism and also cancers of gastrointestinal tract. However, the exact functional roles of HNF4α in prostate cancer progression are still not fully understood. In this study, we determined the functional significance of HNF4α in prostate cancer. Our results showed that HNF4α exhibited a reduced expression pattern in clinical prostate cancer tissues, prostate cancer cell lines and xenograft model of castration-relapse prostate cancer. Stable HNF4α knockdown not only could promote cell proliferation and suppress doxorubicin (Dox)-induced cellular senescence in prostate cancer cells, but also confer resistance to paclitaxel treatment and enhance colony formation capacity and in vivo tumorigenicity of prostate cancer cells. On the contrary, ectopic overexpression of HNF4α could significantly inhibit the cell proliferation of prostate cancer cells, induce cell-cycle arrest at G(2)/M phase and trigger the cellular senescence in prostate cancer cells by activation of p21 signal pathway in a p53-independent manner via its direct transactivation of CDKN1A. Together, our results show that HNF4α performs a tumor suppressor function in prostate cancer via a mechanism of p21-driven cellular senescence. Nature Publishing Group UK 2019-11-06 2020 /pmc/articles/PMC7018660/ /pubmed/31695151 http://dx.doi.org/10.1038/s41388-019-1080-3 Text en © The Author(s) 2019 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wang, Zhu
Li, Youjia
Wu, Dinglan
Yu, Shan
Wang, Yuliang
Leung Chan, Franky
Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence
title Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence
title_full Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence
title_fullStr Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence
title_full_unstemmed Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence
title_short Nuclear receptor HNF4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence
title_sort nuclear receptor hnf4α performs a tumor suppressor function in prostate cancer via its induction of p21-driven cellular senescence
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018660/
https://www.ncbi.nlm.nih.gov/pubmed/31695151
http://dx.doi.org/10.1038/s41388-019-1080-3
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