Abstract LB-075: The histone demethylase JMJD1A is essential to prostate cancer cells through regulation of c-Myc expression

Abstract

Abstract Histone demethylase JMJD1A controls gene expression by epigenetic regulation of H3K9 methylation marks. To investigate role of JMJD1A in the development and progression of prostate cancer, we knock down JMJD1A in prostate cancer cells and examine its effect on gene expression and cancer cell biology. We find that silencing of JMJD1A results in the lethality of prostate cancer cells concomitant with inhibition of cell proliferation, induction of apoptosis and cell cycle arrest. Profiling array analyses reveal c-Myc as one of the top transcriptional networks altered upon the JMJD1A inhibition. The gene ontology pathway analyses show that the primary functions of c-Myc targets regulated by JMJD1A are related to cell cycle, cell proliferation and cell survival. Mechanistically, JMJD1A promotes the recruitment of AR and induces demethylation at the c-Myc gene enhancer, thereby increasing the AR-dependent transcription of c-Myc mRNA. In a parallel pathway, JMJD1A binds to E3 ubiquitin ligase HUWE1, attenuates the HUWE1-induced degradation of c-Myc, and thus increases the c-Myc protein level. Together, JMJD1A controls the expression of c-Myc at transcriptional and post-translational levels. Re-expression of c-Myc in the JMJD1A-knockdown cells partly recues the growth of prostate cancer cells in vitro and in vivo. The protein level of c-Myc is positively correlated with that of JMJD1A in a subset of human prostate cancer specimens. Collectively, our findings identify a critical role of JMJD1A for the viability of prostate cancer cells through regulation of c-Myc expression. Note: This abstract was not presented at the meeting. Citation Format: Lingling Fan, Guihong Peng, Natasha Sahgal, Ladan Fazli, Martin Gleave, Yuji Zhang, Arif Hussain, Jianfei Qi. The histone demethylase JMJD1A is essential to prostate cancer cells through regulation of c-Myc expression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-075. doi:10.1158/1538-7445.AM2015-LB-075