Runx3 inactivation is a crucial early event in the development of lung adenocarcinoma

Cancer Cell. 2013 Nov 11;24(5):603-16. doi: 10.1016/j.ccr.2013.10.003.

Abstract

Targeted inactivation of Runx3 in mouse lung induced mucinous and nonmucinous adenomas and markedly shortened latency of adenocarcinoma formation induced by oncogenic K-Ras. RUNX3 was frequently inactivated in K-RAS mutated human lung adenocarcinomas. A functional genetic screen of a fly mutant library and molecular analysis in cultured cell lines revealed that Runx3 forms a complex with BRD2 in a K-Ras-dependent manner in the early phase of the cell cycle; this complex induces expression of p14(ARF)/p19(Arf) and p21(WAF/CIP). When K-Ras was constitutively activated, the Runx3-BRD2 complex was stably maintained and expression of both p14(ARF) and p21(WAF/CIP) was prolonged. These results provide a missing link between oncogenic K-Ras and the p14(ARF)-p53 pathway, and may explain how cells defend against oncogenic K-Ras.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / metabolism
  • Acetylation
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma of Lung
  • Alveolar Epithelial Cells / physiology
  • Animals
  • Carcinogenesis / metabolism
  • Cell Differentiation
  • Cell Line, Tumor
  • Core Binding Factor Alpha 3 Subunit / genetics
  • Core Binding Factor Alpha 3 Subunit / metabolism*
  • Cyclin D1 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Gene Expression
  • Gene Knockout Techniques
  • HEK293 Cells
  • Histone Deacetylases / metabolism
  • Humans
  • Lung Neoplasms / metabolism*
  • Mice
  • Mice, Transgenic
  • Protein Processing, Post-Translational
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • Repressor Proteins / metabolism
  • Respiratory Mucosa / pathology
  • Transcription Factors
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • BRD2 protein, human
  • CCND1 protein, human
  • CDKN1A protein, human
  • Core Binding Factor Alpha 3 Subunit
  • Cyclin-Dependent Kinase Inhibitor p21
  • KRAS protein, human
  • Proto-Oncogene Proteins
  • Repressor Proteins
  • Runx3 protein, human
  • Runx3 protein, mouse
  • Transcription Factors
  • Cyclin D1
  • Protein-Serine-Threonine Kinases
  • HDAC4 protein, human
  • Histone Deacetylases
  • ADP-Ribosylation Factors
  • Hras protein, mouse
  • Proto-Oncogene Proteins p21(ras)
  • ras Proteins