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Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival
The histone demethylase JMJD1A, which controls gene expression by epigenetic regulation of H3K9 methylation marks, functions in diverse activities, including spermatogenesis, metabolism, and stem cell self-renewal and differentiation. Here, we found that JMJD1A knockdown in prostate cancer cells ant...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2015
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757517/ https://www.ncbi.nlm.nih.gov/pubmed/26279298 http://dx.doi.org/10.1038/onc.2015.309 |
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author | Fan, Lingling Peng, Guihong Sahgal, Natasha Fazli, Ladan Gleave, Martin Zhang, Yuji Hussain, Arif Qi, Jianfei |
author_facet | Fan, Lingling Peng, Guihong Sahgal, Natasha Fazli, Ladan Gleave, Martin Zhang, Yuji Hussain, Arif Qi, Jianfei |
author_sort | Fan, Lingling |
collection | PubMed |
description | The histone demethylase JMJD1A, which controls gene expression by epigenetic regulation of H3K9 methylation marks, functions in diverse activities, including spermatogenesis, metabolism, and stem cell self-renewal and differentiation. Here, we found that JMJD1A knockdown in prostate cancer cells antagonizes their proliferation and survival. Profiling array analyses revealed that JMJD1A-dependent genes function in cellular growth, proliferation and survival, and implicated that the c-Myc transcriptional network is de-regulated following JMJD1A inhibition. Biochemical analyses confirmed that JMJD1A enhances c-Myc transcriptional activity by upregulating c-Myc expression levels. Mechanistically, JMJD1A activity promoted recruitment of androgen receptor (AR) to the c-Myc gene enhancer and induced H3K9 demethylation, increasing AR-dependent transcription of c-Myc mRNA. In parallel, we found that JMJD1A regulated c-Myc stability, likely by inhibiting HUWE1, an E3 ubiquitin ligase known to target degradation of several substrates including c-Myc. JMJD1A (wild-type or mutant lacking histone demethylase activity) bound to HUWE1, attenuated HUWE1-dependent ubiquitination and subsequent degradation of c-Myc, increasing c-Myc protein levels. Furthermore, c-Myc knockdown in prostate cancer cells phenocopied effects of JMJD1A knockdown, and c-Myc re-expression in JMJD1A-knockdown cells partially rescued prostate cancer cell growth in vitro and in vivo. c-Myc protein levels were positively correlated with those of JMJD1A in a subset of human prostate cancer specimens. Collectively, our findings identify a critical role for JMJD1A in regulating proliferation and survival of prostate cancer cells by controlling c-Myc expression at transcriptional and post-translational levels. |
format | Online Article Text |
id | pubmed-4757517 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
record_format | MEDLINE/PubMed |
spelling | pubmed-47575172016-05-18 Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival Fan, Lingling Peng, Guihong Sahgal, Natasha Fazli, Ladan Gleave, Martin Zhang, Yuji Hussain, Arif Qi, Jianfei Oncogene Article The histone demethylase JMJD1A, which controls gene expression by epigenetic regulation of H3K9 methylation marks, functions in diverse activities, including spermatogenesis, metabolism, and stem cell self-renewal and differentiation. Here, we found that JMJD1A knockdown in prostate cancer cells antagonizes their proliferation and survival. Profiling array analyses revealed that JMJD1A-dependent genes function in cellular growth, proliferation and survival, and implicated that the c-Myc transcriptional network is de-regulated following JMJD1A inhibition. Biochemical analyses confirmed that JMJD1A enhances c-Myc transcriptional activity by upregulating c-Myc expression levels. Mechanistically, JMJD1A activity promoted recruitment of androgen receptor (AR) to the c-Myc gene enhancer and induced H3K9 demethylation, increasing AR-dependent transcription of c-Myc mRNA. In parallel, we found that JMJD1A regulated c-Myc stability, likely by inhibiting HUWE1, an E3 ubiquitin ligase known to target degradation of several substrates including c-Myc. JMJD1A (wild-type or mutant lacking histone demethylase activity) bound to HUWE1, attenuated HUWE1-dependent ubiquitination and subsequent degradation of c-Myc, increasing c-Myc protein levels. Furthermore, c-Myc knockdown in prostate cancer cells phenocopied effects of JMJD1A knockdown, and c-Myc re-expression in JMJD1A-knockdown cells partially rescued prostate cancer cell growth in vitro and in vivo. c-Myc protein levels were positively correlated with those of JMJD1A in a subset of human prostate cancer specimens. Collectively, our findings identify a critical role for JMJD1A in regulating proliferation and survival of prostate cancer cells by controlling c-Myc expression at transcriptional and post-translational levels. 2015-08-17 2016-05-12 /pmc/articles/PMC4757517/ /pubmed/26279298 http://dx.doi.org/10.1038/onc.2015.309 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download 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 |
spellingShingle | Article Fan, Lingling Peng, Guihong Sahgal, Natasha Fazli, Ladan Gleave, Martin Zhang, Yuji Hussain, Arif Qi, Jianfei Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival |
title | Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival |
title_full | Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival |
title_fullStr | Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival |
title_full_unstemmed | Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival |
title_short | Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival |
title_sort | regulation of c-myc expression by the histone demethylase jmjd1a is essential for prostate cancer cell growth and survival |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4757517/ https://www.ncbi.nlm.nih.gov/pubmed/26279298 http://dx.doi.org/10.1038/onc.2015.309 |
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