The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression

Yang Wang; Dan Chen; Haili Qian; Yihsuan S Tsai; Shujuan Shao; Quentin Liu; Daniel Dominguez; Zefeng Wang

doi:10.1016/j.ccr.2014.07.010

The splicing factor RBM4 controls apoptosis, proliferation, and migration to suppress tumor progression

Cancer Cell. 2014 Sep 8;26(3):374-389. doi: 10.1016/j.ccr.2014.07.010.

Authors

Yang Wang¹, Dan Chen², Haili Qian³, Yihsuan S Tsai⁴, Shujuan Shao⁵, Quentin Liu⁶, Daniel Dominguez⁴, Zefeng Wang⁷

Affiliations

¹ 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.
² Department of Pathology, First Affiliated Hospital. Dalian Medical University, Dalian 116001, China.
³ State Key Laboratory of Molecular Oncology, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100021, China.
⁴ Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA.
⁵ Key Laboratory of Proteomics of Liaoning Province, Dalian Medical University, Dalian 116044, China.
⁶ Institute of Cancer Stem Cell, Second Affiliated Hospital, Cancer Center, Dalian Medical University, Dalian 116044, China.
⁷ Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA. Electronic address: zefeng@med.unc.edu.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Alternative Splicing
Animals
Apoptosis*
Base Sequence
Carcinoma, Non-Small-Cell Lung / metabolism*
Carcinoma, Non-Small-Cell Lung / mortality
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Movement*
Cell Proliferation*
Disease Progression
Enzyme Activation
Female
Gene Expression Regulation, Neoplastic
Humans
Kaplan-Meier Estimate
Lung Neoplasms / metabolism*
Lung Neoplasms / mortality
Lung Neoplasms / pathology
Mice
Mice, Nude
Neoplasm Transplantation
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
RNA-Binding Proteins / genetics
RNA-Binding Proteins / metabolism
RNA-Binding Proteins / physiology*
Serine-Arginine Splicing Factors
TOR Serine-Threonine Kinases / metabolism
Transcriptome
Tumor Burden
Tumor Suppressor Proteins / physiology
bcl-X Protein / genetics
bcl-X Protein / metabolism

Substances

Nuclear Proteins
RBM4 protein, human
RNA-Binding Proteins
Tumor Suppressor Proteins
bcl-X Protein
Serine-Arginine Splicing Factors
MTOR protein, human
TOR Serine-Threonine Kinases

Associated data

GEO/GSE58594

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding