CSN6 drives carcinogenesis by positively regulating Myc stability

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 () and Mong-Hong Lee ()
Additional contact information
Jian Chen: The University of Texas MD Anderson Cancer Center
Ji-Hyun Shin: The University of Texas MD Anderson Cancer Center
Ruiying Zhao: The University of Texas MD Anderson Cancer Center
Liem Phan: The University of Texas MD Anderson Cancer Center
Hua Wang: The University of Texas MD Anderson Cancer Center
Yuwen Xue: The University of Texas MD Anderson Cancer Center
Sean M. Post: The University of Texas MD Anderson Cancer Center
Hyun Ho Choi: The University of Texas MD Anderson Cancer Center
Jiun-Sheng Chen: The University of Texas MD Anderson Cancer Center
Edward Wang: The University of Texas MD Anderson Cancer Center
Zhongguo Zhou: The University of Texas MD Anderson Cancer Center
Chieh Tseng: The University of Texas MD Anderson Cancer Center
Christopher Gully: The University of Texas MD Anderson Cancer Center
Guermarie Velazquez-Torres: The University of Texas MD Anderson Cancer Center
Enrique Fuentes-Mattei: The University of Texas MD Anderson Cancer Center
Giselle Yeung: The University of Texas MD Anderson Cancer Center
Yi Qiao: The University of Texas MD Anderson Cancer Center
Ping-Chieh Chou: The University of Texas MD Anderson Cancer Center
Chun-Hui Su: The University of Texas MD Anderson Cancer Center
Yun-Chih Hsieh: The University of Texas MD Anderson Cancer Center
Shih-Lan Hsu: Taichung Veterans General Hospital, No. 160, Section 3, Chung-Gang Road, Taichung, 40705 Taiwan, ROC
Kazufumi Ohshiro: The University of Texas MD Anderson Cancer Center
Tattym Shaikenov: The University of Texas MD Anderson Cancer Center
Huamin Wang: The University of Texas MD Anderson Cancer Center
Sai-Ching Jim Yeung: The University of Texas MD Anderson Cancer Center
Mong-Hong Lee: The University of Texas MD Anderson Cancer Center

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6384

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