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.


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


  • 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