title: Snail recruits Ring1B to mediate transcriptional repression and cell migration in pancreatic cancer cells.
abstract: Transcriptional repressor Snail is a master regulator of epithelial-mesenchymal transition (EMT), yet the epigenetic mechanism governing Snail to induce EMT is not well understood. Here, we report that in pancreatic ductal adenocarcinoma (PDAC), elevated levels of the ubiquitin E3 ligase Ring1B and Snail, along with elevated monoubiquitination of H2A at K119 (H2AK119Ub1), are highly correlated with poor survival. Mechanistic investigations identified Ring1B as a Snail-interacting protein and showed that the carboxyl zinc fingers of Snail recruit Ring1B and its paralog Ring1A to repress its target promoters. Simultaneous depletion of Ring1A and Ring1B in pancreatic cancer cells decreased Snail binding to the target chromatin, abolished H2AK119Ub1 modification, and thereby compromised Snail-mediated transcriptional repression and cell migration. We found that Ring1B and the SNAG-associated chromatin modifier EZH2 formed distinct protein complexes with Snail and that EZH2 was required for Snail-Ring1A/B recruitment to the target promoter. Collectively, our results unravel an epigenetic mechanism underlying transcriptional repression by Snail, suggest Ring1A/B as a candidate therapeutic target, and identify H2AK119Ub1 as a potential biomarker for PDAC diagnosis and prognosis.
authors.affiliation: Department of Surgery, Ruijin Hospital, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China. Department of Hepatobiliary Surgery, Union Hospital, Fujian Medical University, Fuzhou, China.
authors.forename: Jiangzhi
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Surgery, Ruijin Hospital, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Surgery, Ruijin Hospital, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Xiuqun
authors.initials: X
authors.lastname: Zou
authors.affiliation: Department of Surgery, Ruijin Hospital, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Surgery, Ruijin Hospital, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Surgery, Ruijin Hospital, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Surgery, Ruijin Hospital, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Baiyong
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Surgery, Ruijin Hospital, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Xiaxing
authors.initials: X
authors.lastname: Deng
authors.affiliation: Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Aiwu
authors.initials: A
authors.lastname: Zhou
authors.affiliation: Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Y Eugene
authors.initials: YE
authors.lastname: Chin
authors.affiliation: Institute of Health Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Rauscher
authors.affiliation: Department of Surgery, Ruijin Hospital, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China. houzy@sjtu.edu.cn chhpeng@yearh.net.
authors.forename: Chenghong
authors.initials: C
authors.lastname: Peng
authors.affiliation: Department of Surgery, Ruijin Hospital, Department of Biochemistry and Molecular Cell Biology, Shanghai Jiaotong University School of Medicine, Shanghai, China. Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiaotong University School of Medicine, Shanghai, China. houzy@sjtu.edu.cn chhpeng@yearh.net.
authors.forename: Zhaoyuan
authors.initials: Z
authors.lastname: Hou
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D000071221:Enhancer of Zeste Homolog 2 Protein; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D063151:Polycomb Repressive Complex 2 / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D000071250:Snail Family Transcription Factors; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D063150:Polycomb Repressive Complex 1; C489841:RNF2 protein, human