Sun Jie, Shen Qi, Lu Haiqi, Jiang Zhinong, Xu Wenxia, Feng Lifeng, Li Ling, Wang Xian, Cai Xiujun, Jin Hongchuan
Laboratory of Cancer Biology, Provincial Key Lab of Biotherapy in Zhejiang, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
Department of Medical Oncology, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
Oncotarget. 2015 Dec 8;6(39):41997-2007. doi: 10.18632/oncotarget.6015.
Ras is aberrantly activated in many cancers and active DNA demethylation plays a fundamental role to establish DNA methylation pattern which is of importance to cancer development. However, it was unknown whether and how Ras regulate DNA demethylation during carcinogenesis. Here we found that Ras downregulated thymine-DNA glycosylase (TDG), a DNA demethylation enzyme, by inhibiting the interaction of transcription activator ING4 with TDG promoter. TDG recruited histone lysine demethylase JMJD3 to the Fas promoter and activated its expression, thus restoring sensitivity to apoptosis. TDG suppressed in vivo tumorigenicity of xenograft pancreatic cancer. Thus, we speculate that reversing Ras-mediated ING4 inhibition to activate Fas expression is a potential therapeutic approach for Ras-driven cancers.
Ras在许多癌症中被异常激活，而活性DNA去甲基化在建立对癌症发展至关重要的DNA甲基化模式中起着基本作用。然而，在致癌过程中Ras是否以及如何调节DNA去甲基化尚不清楚。在此我们发现，Ras通过抑制转录激活因子ING4与TDG启动子的相互作用来下调胸腺嘧啶-DNA糖基化酶（TDG），一种DNA去甲基化酶。TDG将组蛋白赖氨酸去甲基化酶JMJD3募集到Fas启动子并激活其表达，从而恢复对凋亡的敏感性。TDG抑制异种移植胰腺癌的体内致瘤性。因此，我们推测逆转Ras介导的ING4抑制以激活Fas表达是Ras驱动型癌症的一种潜在治疗方法。
