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CSN6 drives carcinogenesis by positively regulating Myc stability.

Nature communications (2014-11-15)
Jian Chen, Ji-Hyun Shin, Ruiying Zhao, Liem Phan, Hua Wang, Yuwen Xue, Sean M Post, Hyun Ho Choi, Jiun-Sheng Chen, Edward Wang, Zhongguo Zhou, Chieh Tseng, Christopher Gully, Guermarie Velazquez-Torres, Enrique Fuentes-Mattei, Giselle Yeung, Yi Qiao, Ping-Chieh Chou, Chun-Hui Su, Yun-Chih Hsieh, Shih-Lan Hsu, Kazufumi Ohshiro, Tattym Shaikenov, Huamin Wang, Sai-Ching Jim Yeung, Mong-Hong Lee
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.

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