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Published on: December 19, 2019
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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
Summary
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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