title: The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression.
abstract: Splicing dysregulation is one of the molecular hallmarks of cancer. However, the underlying molecular mechanisms remain poorly defined. Here we report that the splicing factor RBM4 suppresses proliferation and migration of various cancer cells by specifically controlling cancer-related splicing. Particularly, RBM4 regulates Bcl-x splicing to induce apoptosis, and coexpression of Bcl-xL partially reverses the RBM4-mediated tumor suppression. Moreover, RBM4 antagonizes an oncogenic splicing factor, SRSF1, to inhibit mTOR activation. Strikingly, RBM4 expression is decreased dramatically in cancer patients, and the RBM4 level correlates positively with improved survival. In addition to providing mechanistic insights of cancer-related splicing dysregulation, this study establishes RBM4 as a tumor suppressor with therapeutic potential and clinical values as a prognostic factor.
authors.affiliation: Institute of Cancer Stem Cell, Second Affiliated Hospital, Cancer Center, Dalian Medical University, Dalian 116044, China; Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: yangwang@dlmedu.edu.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, First Affiliated Hospital. Dalian Medical University, Dalian 116001, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Molecular Oncology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, China.
authors.forename: Haili
authors.initials: H
authors.lastname: Qian
authors.affiliation: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Yihsuan S
authors.initials: YS
authors.lastname: Tsai
authors.affiliation: Key Laboratory of Proteomics of Liaoning Province, Dalian Medical University, Dalian 116044, China.
authors.forename: Shujuan
authors.initials: S
authors.lastname: Shao
authors.affiliation: Institute of Cancer Stem Cell, Second Affiliated Hospital, Cancer Center, Dalian Medical University, Dalian 116044, China.
authors.forename: Quentin
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Dominguez
authors.affiliation: Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: zefeng@med.unc.edu.
authors.forename: Zefeng
authors.initials: Z
authors.lastname: Wang
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000068103:Serine-Arginine Splicing Factors; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D059467:Transcriptome; D047368:Tumor Burden; D025521:Tumor Suppressor Proteins / Q000502:physiology; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D009687:Nuclear Proteins; C473692:RBM4 protein, human; D016601:RNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D051020:bcl-X Protein; D000068103:Serine-Arginine Splicing Factors; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases