title: Oncogenic Ras suppresses ING4-TDG-Fas axis to promote apoptosis resistance.
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.
authors.affiliation: Laboratory of Cancer Biology, Provincial Key Lab of Biotherapy in Zhejiang, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Medical Oncology, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Shen
authors.affiliation: Department of Medical Oncology, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
authors.forename: Haiqi
authors.initials: H
authors.lastname: Lu
authors.affiliation: Department of Pathology, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
authors.forename: Zhinong
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Laboratory of Cancer Biology, Provincial Key Lab of Biotherapy in Zhejiang, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Xu
authors.affiliation: Laboratory of Cancer Biology, Provincial Key Lab of Biotherapy in Zhejiang, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Feng
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
authors.forename: Xian
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Cai
authors.affiliation: Laboratory of Cancer Biology, Provincial Key Lab of Biotherapy in Zhejiang, Sir Runrun Shaw Hospital, Medical School of Zhejiang University, Hangzhou, China.
authors.forename: Hongchuan
authors.initials: H
authors.lastname: Jin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D044502:Thymine DNA Glycosylase / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C491901:FAS protein, human; D018398:Homeodomain Proteins; C483230:ING4 protein, human; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; D056484:Jumonji Domain-Containing Histone Demethylases; C524220:KDM6B protein, human; D044502:Thymine DNA Glycosylase; D018631:ras Proteins
keywords: ING4; Ras; TDG; oncogenesis