RUNX3 inactivates oncogenic MYC through disruption of MYC/MAX complex and subsequent recruitment of GSK3β-FBXW7 cascade

Commun Biol. 2023 Jul 3;6(1):689. doi: 10.1038/s42003-023-05037-0.

Abstract

MYC is one of the most commonly dysregulated proto-oncogenes in cancer. MYC promotes cancer initiation and maintenance by regulating multiple biological processes, such as proliferation and stem cell function. Here, we show that developmental regulator RUNX3 targets MYC protein for rapid degradation through the glycogen synthase kinase-3 beta-F-box/WD repeat-containing protein 7 (GSK3β-FBXW7) proteolytic pathway. The evolutionarily conserved Runt domain of RUNX3 interacts directly with the basic helix-loop-helix leucine zipper of MYC, resulting in the disruption of MYC/MAX and MYC/MIZ-1 interactions, enhanced GSK3β-mediated phosphorylation of MYC protein at threonine-58 and its subsequent degradation via the ubiquitin-proteasomal pathway. We therefore uncover a previously unknown mode of MYC destabilization by RUNX3 and provide an explanation as to why RUNX3 inhibits early-stage cancer development in gastrointestinal and lung mouse cancer models.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Nucleus* / metabolism
  • Core Binding Factor Alpha 3 Subunit* / genetics
  • Core Binding Factor Alpha 3 Subunit* / metabolism
  • F-Box-WD Repeat-Containing Protein 7 / metabolism
  • Glycogen Synthase Kinase 3 beta / genetics
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Lung Neoplasms* / genetics
  • Lung Neoplasms* / metabolism
  • Mice
  • Proteolysis

Substances

  • F-Box-WD Repeat-Containing Protein 7
  • Glycogen Synthase Kinase 3 beta
  • Runx3 protein, mouse
  • Core Binding Factor Alpha 3 Subunit
  • Myc protein, mouse
  • Max protein, mouse