CD36 inhibits β-catenin/c-myc-mediated glycolysis through ubiquitination of GPC4 to repress colorectal tumorigenesis

Nat Commun. 2019 Sep 4;10(1):3981. doi: 10.1038/s41467-019-11662-3.

Abstract

The diverse expression pattern of CD36 reflects its multiple cellular functions. However, the roles of CD36 in colorectal cancer (CRC) remain unknown. Here, we discover that CD36 expression is progressively decreased from adenomas to carcinomas. CD36 loss predicts poor survival of CRC patients. In CRC cells, CD36 acts as a tumor suppressor and inhibits aerobic glycolysis in vitro and in vivo. Mechanically, CD36-Glypcian 4 (GPC4) interaction could promote the proteasome-dependent ubiquitination of GPC4, followed by inhibition of β-catenin/c-myc signaling and suppression of downstream glycolytic target genes GLUT1, HK2, PKM2 and LDHA. Moreover, disruption of CD36 in inflammation-induced CRC model as well as ApcMin/+ mice model significantly increased colorectal tumorigenesis. Our results reveal a CD36-GPC4-β-catenin-c-myc signaling axis that regulates glycolysis in CRC development and may provide an intervention strategy for CRC prevention.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Animals
  • CD36 Antigens / genetics*
  • CD36 Antigens / metabolism
  • Caco-2 Cells
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / therapy
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic*
  • Glycolysis / genetics*
  • Glypicans / genetics*
  • Glypicans / metabolism
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Male
  • Mice, Inbred BALB C
  • Mice, Nude
  • Middle Aged
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNAi Therapeutics / methods
  • Signal Transduction / genetics
  • Ubiquitination
  • Xenograft Model Antitumor Assays / methods
  • beta Catenin / genetics*
  • beta Catenin / metabolism

Substances

  • CD36 Antigens
  • GPC4 protein, human
  • Glypicans
  • Proto-Oncogene Proteins c-myc
  • beta Catenin