Hu Dongli, Jablonowski Carolyn, Cheng Pei-Hsin, AlTahan Alaa, Li Chunliang, Wang Yingdi, Palmer Lance, Lan Cuixia, Sun Bingmei, Abu-Zaid Ahmed, Fan Yiping, Brimble Mark, Gamboa Nicolas T, Kumbhar Ramhari C, Yanishevski David, Miller Kyle M, Kang Guolian, Zambetti Gerard P, Chen Taosheng, Yan Qin, Davidoff Andrew M, Yang Jun
Department of Surgery, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
Department of Tumor Cell Biology, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
iScience. 2018 Nov 30;9:84-100. doi: 10.1016/j.isci.2018.10.012. Epub 2018 Oct 17.
The p53 tumor suppressor pathway is frequently inactivated in human cancers. However, there are some cancer types without commonly recognized alterations in p53 signaling. Here we report that histone demethylase KDM5A is involved in the regulation of p53 activity. KDM5A is significantly amplified in multiple types of cancers, an event that tends to be mutually exclusive to p53 mutation. We show that KDM5A acts as a negative regulator of p53 signaling through inhibition of p53 translation via suppression of a subgroup of eukaryotic translation initiation genes. Genetic deletion of KDM5A results in upregulation of p53 in multiple lineages of cancer cells and inhibits tumor growth in a p53-dependent manner. In addition, we have identified a regulatory loop between p53, miR-34, and KDM5A, whereby the induction of miR-34 leads to suppression of KDM5A. Thus, our findings reveal a mechanism by which KDM5A inhibits p53 translation to modulate cancer progression.
p53肿瘤抑制通路在人类癌症中常常失活。然而，有一些癌症类型在p53信号传导中没有常见的公认改变。在此我们报告组蛋白去甲基化酶KDM5A参与p53活性的调控。KDM5A在多种癌症类型中显著扩增，这一事件往往与p53突变相互排斥。我们表明KDM5A通过抑制真核翻译起始基因的一个亚组来抑制p53翻译，从而作为p53信号传导的负调节因子。KDM5A的基因缺失导致多种癌细胞系中p53上调，并以p53依赖的方式抑制肿瘤生长。此外，我们鉴定出p53、miR-34和KDM5A之间的一个调节环，其中miR-34的诱导导致KDM5A的抑制。因此，我们的发现揭示了一种KDM5A抑制p53翻译以调节癌症进展的机制。
