CSN6 drives carcinogenesis by positively regulating Myc stability

Nat Commun. 2014 Nov 14;5:5384. doi: 10.1038/ncomms6384.

Abstract

Cullin-RING ubiquitin ligases (CRLs) are critical in ubiquitinating Myc, while COP9 signalosome (CSN) controls neddylation of Cullin in CRL. The mechanistic link between Cullin neddylation and Myc ubiquitination/degradation is unclear. Here we show that Myc is a target of the CSN subunit 6 (CSN6)-Cullin signalling axis and that CSN6 is a positive regulator of Myc. CSN6 enhanced neddylation of Cullin-1 and facilitated autoubiquitination/degradation of Fbxw7, a component of CRL involved in Myc ubiquitination, thereby stabilizing Myc. Csn6 haplo-insufficiency decreased Cullin-1 neddylation but increased Fbxw7 stability to compromise Myc stability and activity in an Eμ-Myc mouse model, resulting in decelerated lymphomagenesis. We found that CSN6 overexpression, which leads to aberrant expression of Myc target genes, is frequent in human cancers. Together, these results define a mechanism for the regulation of Myc stability through the CSN-Cullin-Fbxw7 axis and provide insights into the correlation of CSN6 overexpression with Myc stabilization/activation during tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • COP9 Signalosome Complex
  • Carcinogenesis / genetics*
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / physiology
  • Gene Knockdown Techniques
  • Lymphoma / metabolism
  • Lymphoma / physiopathology
  • Mice
  • Mice, Transgenic / genetics
  • Neoplasms, Experimental / genetics
  • Peptide Hydrolases / biosynthesis
  • Peptide Hydrolases / physiology*
  • Proto-Oncogene Proteins c-myc / biosynthesis
  • Proto-Oncogene Proteins c-myc / physiology*
  • SKP Cullin F-Box Protein Ligases / physiology
  • Transcription, Genetic / physiology
  • Ubiquitination

Substances

  • Adaptor Proteins, Signal Transducing
  • Cops6 protein, mouse
  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • SKP Cullin F-Box Protein Ligases
  • Peptide Hydrolases
  • COP9 Signalosome Complex