The JMJD2A demethylase regulates apoptosis and proliferation in colon cancer cells
The JMJD2A demethylase regulates apoptosis and proliferation in colon cancer cells
复制标题
DOI：
10.1002/jcb.24009
复制
发表时间：
2012-04-01
影响因子：
4
通讯作者：
Janknecht, Ralf
中科院分区：
文献类型：
--
作者：
Kim, Tae-Dong;Shin, Sook;Janknecht, Ralf
JMJD2A是一种转录辅因子和酶，催化组蛋白H3赖氨酸9和36的去甲基化，在人类肿瘤中过表达，但其在肿瘤发生中的作用尚不清楚。在这里，我们证明了JMJD2A在体外和在HCT116结肠癌细胞中都与肿瘤抑制基因P53相互作用。染色质免疫沉淀分析表明，在DNA损伤剂阿霉素刺激下，JMJD2A与P53一起被招募到p21细胞周期抑制因子的启动子。JMJD2A表达下调导致p21和促凋亡Puma蛋白表达增加，而抗凋亡蛋白Bcl2表达水平降低。在低血清培养条件下，JMJD2A基因的过表达可抑制HCT116、DLD-1和HT-29细胞的增殖，而过表达则促进HCT116细胞的增殖。最后，JMJD2A的缺失诱导了HCT116细胞的凋亡，在没有P53的情况下，这种影响不那么明显。总之，这些数据表明JMJD2A是一种新的结肠癌细胞增殖和存活的启动子，它以P53依赖和非依赖的方式介导其作用。因此，JMJD2A可能是使肿瘤细胞对化疗诱导的细胞死亡和生长抑制敏感的有效靶点。J.细胞。生物化学。2012年，113：13681376。(C)2011年威利期刊公司。
JMJD2A is a transcriptional cofactor and enzyme that catalyzes demethylation of histone H3 lysines 9 and 36 and is overexpressed in human tumors, but its role in oncogenesis remains unclear. Here, we show that JMJD2A interacts with the tumor suppressor p53 both in vitro and in HCT116 colon cancer cells. Chromatin immunoprecipitation assays demonstrated that JMJD2A was recruited together with p53 to the promoter of the p21 cell cycle inhibitor upon stimulation with the DNA damaging agent, adriamycin. Downregulation of JMJD2A resulted in increased expression of p21 and of the pro-apoptotic Puma protein, whereas levels of the anti-apoptotic Bcl-2 protein were decreased. Furthermore, JMJD2A knock-down led to reduced HCT116, DLD-1 and HT-29 colon cancer cell proliferation, while overexpression of JMJD2A enhanced HCT116 proliferation in low serum media. Finally, JMJD2A depletion induced apoptosis in HCT116 cells and this effect was less pronounced in the absence of p53. Collectively, these data indicate that JMJD2A is a novel promoter of colon cancer cell proliferation and survival, which mediates its effects in p53-dependent and -independent ways. JMJD2A may therefore be a valid target to sensitize tumor cells to chemotherapy-induced cell death and growth suppression. J. Cell. Biochem. 113: 13681376, 2012. (c) 2011 Wiley Periodicals, Inc.