Oncogenic Ras suppresses ING4-TDG-Fas axis to promote apoptosis resistance.
Oncogenic Ras suppresses ING4-TDG-Fas axis to promote apoptosis resistance.
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致癌Ras抑制ING4-TDG-Fas轴促进细胞凋亡抵抗
DOI：
10.18632/oncotarget.6015
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发表时间：
2015-12-08
期刊：
影响因子：
--
通讯作者：
Jin H
中科院分区：
文献类型：
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作者：
Sun J;Shen Q;Lu H;Jiang Z;Xu W;Feng L;Li L;Wang X;Cai X;Jin H
Ras在许多癌症中异常激活，活性DNA去甲基化在建立DNA甲基化模式中起基础作用，DNA甲基化模式在癌症发展中具有重要意义。然而，Ras是否以及如何在癌变过程中调节DNA去甲基化尚不清楚。我们发现Ras通过抑制转录激活因子ING 4与胸腺嘧啶-DNA糖基化酶（TDG）启动子的相互作用，下调TDG的表达。TDG将组蛋白赖氨酸脱甲基酶JMJD 3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ING 4抑制以激活Fas表达是Ras驱动的癌症的潜在治疗方法。
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.