c-MYC-USP49-BAG2 axis promotes proliferation and chemoresistance of colorectal cancer cells in vitro

Biochem Biophys Res Commun. 2022 Jun 4:607:117-123. doi: 10.1016/j.bbrc.2022.03.138. Epub 2022 Mar 27.

Abstract

Deubiquitinases (DUBs) play critical roles in tumorigenesis and are emerging as potential therapeutic targets. However, it remains less clear which DUBs may play important roles and represent a realistic vulnerability for a particular type of tumor. Here we revealed that Ubiquitin Specific Peptidase 49 (USP49) is transcriptionally activated by c-MYC in colorectal cancer (CRC), and CRC patients with elevated USP49 levels exhibited significantly shorter survival. Knockdown of USP49 markedly inhibited CRC cell proliferation, colony formation, and chemotherapy resistance in vitro. Investigation of mechanisms unravels that USP49 deubiquitinates and stabilizes Bcl-2-Associated Athanogene 2 (BAG2), a well-known protein that antagonizes apoptosis and enables adaptive response of CRC cells. This study identified a novel mechanism by which USP49 promotes CRC cell survival by stabilizing BAG2 through the c-MYC-USP49-BAG2 axis, indicating that USP49 may become a potential therapeutic target for CRC.

Keywords: BAG2; Chemotherapy resistance; Colorectal cancer; Deubiquitination; USP49.

MeSH terms

  • Carcinogenesis
  • Cell Line, Tumor
  • Cell Proliferation
  • Colorectal Neoplasms* / genetics
  • Drug Resistance, Neoplasm
  • Humans
  • Molecular Chaperones* / genetics
  • Proto-Oncogene Proteins c-myc* / genetics
  • Ubiquitin Thiolesterase* / genetics

Substances

  • BAG2 protein, human
  • MYC protein, human
  • Molecular Chaperones
  • Proto-Oncogene Proteins c-myc
  • USP49 protein, human
  • Ubiquitin Thiolesterase