Research Papers:
Oncogenic Ras suppresses ING4TDGFas axis to promote apoptosis resistance
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Jie Sun1, Qi Shen2, Haiqi Lu2, Zhinong Jiang3, Wenxia Xu1, Lifeng Feng1, Ling Li4, Xian Wang2, Xiujun Cai5, Hongchuan Jin1
1Laboratory of Cancer Biology, Provincial Key Lab of Biotherapy in Zhejiang, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
2Department of Medical Oncology, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
3Department of Pathology, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
4Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte CA, USA
5Department of General Surgery, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China
Correspondence to:
Dr. Xiujun Cai, e-mail: [email protected]
Dr. Hongchuan Jin, e-mail: [email protected]
Keywords: Ras, TDG, oncogenesis, ING4
Received: July 10, 2015 Accepted: October 12, 2015 Published: October 24, 2015
ABSTRACT
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.