RNA-binding protein SORBS2 suppresses clear cell renal cell carcinoma metastasis by enhancing MTUS1 mRNA stability

Cell Death Dis. 2020 Dec 12;11(12):1056. doi: 10.1038/s41419-020-03268-1.

Abstract

RNA-binding proteins (RBPs) predominantly contribute to abnormal posttranscriptional gene modulation and disease progression in cancer. Sorbin and SH3 domain-containing 2 (SORBS2), an RBP, has been reported to be a potent tumor suppressor in several cancer types. Through integrative analysis of clinical specimens, we disclosed that the expression level of SORBS2 was saliently decreased in metastatic tissues and positively correlated with overall survival. We observed that overexpression of SORBS2 brought about decreased metastatic capacity in ccRCC cell lines. Transcriptome-wide analysis revealed that SORBS2 notably increased microtubule-associated tumor-suppressor 1 gene (MTUS1) expression. In-depth mechanistic exploring discovered that the Cys2-His2 zinc finger (C2H2-ZnF) domain of SORBS2 directly bound to the 3' untranslated region (3'UTR) of MTUS1 mRNA, which increased MTUS1 mRNA stability. In addition, we identified that MTUS1 regulated microtubule dynamics via promoting KIF2CS192 phosphorylation by Aurora B. Together, our research identified SORBS2 as a suppressor of ccRCC metastasis by enhancing MTUS1 mRNA stability, providing a novel understanding of RBPs during ccRCC progression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Aurora Kinase B / metabolism
  • Carcinoma, Renal Cell / genetics*
  • Cell Line, Tumor
  • Down-Regulation / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kinesins / metabolism
  • Male
  • Microtubules / metabolism
  • Middle Aged
  • Phosphorylation
  • Prognosis
  • Protein Binding / genetics
  • RNA Stability / genetics*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / metabolism*
  • Survival Analysis
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism
  • Up-Regulation / genetics

Substances

  • 3' Untranslated Regions
  • Adaptor Proteins, Signal Transducing
  • KIF2C protein, human
  • MTUS1 protein, human
  • RNA, Messenger
  • RNA-Binding Proteins
  • SORBS2 protein, human
  • Tumor Suppressor Proteins
  • Aurora Kinase B
  • Kinesins

Supplementary concepts

  • Clear-cell metastatic renal cell carcinoma