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 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 deregulated 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.
University of Maryland School of Medicine, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
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Fan
University of Maryland School of Medicine, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
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Peng
Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK.
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Sahgal
Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
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Fazli
Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada.
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Gleave
University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, MD, USA.
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Zhang
University of Maryland School of Medicine, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Baltimore VA Medical Center, Baltimore, MD, USA.
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Hussain
University of Maryland School of Medicine, Baltimore, MD, USA.|Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.|Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USA.
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Qi
D063646:Carcinogenesis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D004742:Enhancer Elements, Genetic / Q000235:genetics; D055785:Gene Knockdown Techniques; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D055550:Protein Stability; D021381:Protein Transport; D059748:Proteolysis; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors
C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D011944:Receptors, Androgen; D025521:Tumor Suppressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C530247:KDM3A protein, human; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases