Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival.
Regulation of c-Myc expression by the histone demethylase JMJD1A is essential for prostate cancer cell growth and survival.
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作者：
Fan L;Peng G;Sahgal N;Fazli L;Gleave M;Zhang Y;Hussain A;Qi J
组蛋白去甲基化酶JMJD 1A通过H3 K9甲基化标记的表观遗传调节来控制基因表达，在多种活动中发挥作用，包括精子发生、代谢和干细胞自我更新和分化。在这里，我们发现JMJD 1A在前列腺癌细胞中的敲低拮抗了它们的增殖和存活。分析阵列分析显示JMJD 1A依赖性基因在细胞生长、增殖和存活中起作用，并暗示在JMJD 1A抑制后c-Myc转录网络被去调节。生化分析证实，JMJD 1A通过上调c-Myc表达水平来增强c-Myc转录活性。从机制上讲，JMJD 1A活性促进了雄激素受体（AR）向c-Myc基因增强子的募集，并诱导H3 K9去甲基化，增加了c-Myc mRNA的AR依赖性转录。同时，我们发现JMJD 1A可能通过抑制HUWE 1来调节c-Myc的稳定性，HUWE 1是一种已知靶向降解包括c-Myc在内的几种底物的E3泛素连接酶。JMJD 1A（野生型或缺乏组蛋白脱甲基酶活性的突变体）与HUWE 1结合，减弱HUWE 1依赖性泛素化和随后的c-Myc降解，增加c-Myc蛋白水平。此外，c-Myc在前列腺癌细胞中的敲除表型模仿了JMJD 1A敲除的作用，并且c-Myc在JMJD 1A敲除细胞中的重新表达在体外和体内部分挽救了前列腺癌细胞的生长。c-Myc蛋白水平与人前列腺癌标本亚组中JMJD 1A的水平呈正相关。总的来说，我们的研究结果确定了JMJD 1A通过在转录和翻译后水平控制c-Myc表达来调节前列腺癌细胞增殖和存活的关键作用。
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.