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CSN6 drives carcinogenesis by positively regulating Myc stability

Jian Chen1, Ji-Hyun Shin1, Ruiying Zhao1

  • 1Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

Nature Communications
|November 15, 2014
PubMed

Insights

The COP9 signalosome subunit 6 (CSN6) stabilizes Myc by promoting Cullin neddylation and Fbxw7 degradation. CSN6 overexpression drives Myc-driven cancers, highlighting a novel therapeutic target.

Area of Science:

  • Molecular Biology
  • Cellular Biology
  • Oncology

Background:

  • Cullin-RING ubiquitin ligases (CRLs) ubiquitinate Myc, a key oncogene.
  • The COP9 signalosome (CSN) regulates CRLs via Cullin neddylation.
  • The precise link between Cullin neddylation and Myc ubiquitination/degradation remains elusive.

Purpose of the Study:

  • To elucidate the mechanistic link between CSN-mediated Cullin neddylation and Myc ubiquitination/degradation.
  • To investigate the role of CSN subunit 6 (CSN6) in regulating Myc stability and activity.
  • To explore the implications of the CSN6-Cullin-Fbxw7 axis in cancer development.

Main Methods:

  • Investigated the interaction between CSN6, Cullin-1, and Fbxw7.
  • Utilized an Eμ-Myc mouse model to assess the in vivo effects of Csn6 haplo-insufficiency.
  • Analyzed CSN6 expression levels in human cancer samples.

Main Results:

  • CSN6 enhances Cullin-1 neddylation and promotes Fbxw7 autoubiquitination and degradation, thereby stabilizing Myc.
  • Csn6 haplo-insufficiency in mice reduced Cullin-1 neddylation, increased Fbxw7 stability, and compromised Myc activity, decelerating lymphomagenesis.
  • CSN6 overexpression, associated with aberrant Myc target gene expression, is prevalent in human cancers.

Conclusions:

  • CSN6 acts as a positive regulator of Myc by controlling the CSN-Cullin-Fbxw7 signaling axis.
  • This pathway is crucial for Myc stabilization and activation in tumorigenesis.
  • Targeting CSN6 may offer a therapeutic strategy for Myc-driven cancers.

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