The Arkadia-ESRP2 axis suppresses tumor progression: analyses in clear-cell renal cell carcinoma

Oncogene. 2016 Jul 7;35(27):3514-23. doi: 10.1038/onc.2015.412. Epub 2015 Nov 2.


Tumor-specific alternative splicing is implicated in the progression of cancer, including clear-cell renal cell carcinoma (ccRCC). Using ccRCC RNA sequencing data from The Cancer Genome Atlas, we found that epithelial splicing regulatory protein 2 (ESRP2), one of the key regulators of alternative splicing in epithelial cells, is expressed in ccRCC. ESRP2 mRNA expression did not correlate with the overall survival rate of ccRCC patients, but the expression of some ESRP-target exons correlated with the good prognosis and with the expression of Arkadia (also known as RNF111) in ccRCC. Arkadia physically interacted with ESRP2, induced polyubiquitination and modulated its splicing function. Arkadia and ESRP2 suppressed ccRCC tumor growth in a coordinated manner. Lower expression of Arkadia correlated with advanced tumor stages and poor outcomes in ccRCC patients. This study thus reveals a novel tumor-suppressive role of the Arkadia-ESRP2 axis in ccRCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Blotting, Western
  • Carcinoma, Renal Cell / genetics*
  • Carcinoma, Renal Cell / metabolism
  • Carcinoma, Renal Cell / pathology
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Disease Progression
  • Epithelial Cells / metabolism
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic
  • Gene Ontology
  • HEK293 Cells
  • Humans
  • Kaplan-Meier Estimate
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / metabolism
  • Kidney Neoplasms / pathology
  • MCF-7 Cells
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Prognosis
  • Protein Binding
  • RNA Interference
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination


  • ESRP2 protein, human
  • Nuclear Proteins
  • RNA-Binding Proteins
  • RNF111 protein, human
  • Ubiquitin-Protein Ligases