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CSN6 drives carcinogenesis by positively regulating Myc stability

Author

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  • Jian Chen

    (The University of Texas MD Anderson Cancer Center
    Present address: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA)

  • 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
    The University of Texas MD Anderson Cancer Center)

  • Mong-Hong Lee

    (The University of Texas MD Anderson Cancer Center)

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.

Suggested Citation

  • 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 V, 2014. "CSN6 drives carcinogenesis by positively regulating Myc stability," Nature Communications, Nature, vol. 5(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6384
    DOI: 10.1038/ncomms6384
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    Cited by:

    1. Huilin Jin & Xiaoling Huang & Qihao Pan & Ning Ma & Xiaoshan Xie & Yue Wei & Fenghai Yu & Weijie Wen & Boyu Zhang & Peng Zhang & Xijie Chen & Jie Wang & Ran-yi Liu & Junzhong Lin & Xiangqi Meng & Mong, 2024. "The EIF3H-HAX1 axis increases RAF-MEK-ERK signaling activity to promote colorectal cancer progression," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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