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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Acknowledgements

We thank Dr M.C. Hung, Dr D.F. Lee, Dr J.M. Hsu, Dr H.P. Kuo, Dr Z. Han, Dr H.K. Lin, Dr M. Blonska and Dr Y.W. Wen for technical and material support. We thank Dr G. Lozano for the Eμ-Myc mice. This work was supported by the National Institutes of Health through grant RO1CA089266, by the Fidelity Foundation to M.-H.L., by the Susan G. Komen Breast Cancer Foundation grant KG081048 and by the NIH MDACC Core grant (CA16672).

Author information

Author notes

    • Jian Chen

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

Affiliations

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

    • Jian Chen
    • , Ji-Hyun Shin
    • , Ruiying Zhao
    • , Liem Phan
    • , Yuwen Xue
    • , 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
    • , Kazufumi Ohshiro
    • , Tattym Shaikenov
    •  & Mong-Hong Lee
  2. Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Hua Wang
  3. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Sean M. Post
  4. Department of Education and Research, Taichung Veterans General Hospital, No. 160, Section 3, Chung-Gang Road, Taichung, 40705 Taiwan, ROC

    • Shih-Lan Hsu
  5. Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Huamin Wang
  6. Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Sai-Ching Jim Yeung
  7. Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA

    • Sai-Ching Jim Yeung

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Contributions

J.C. performed most of the experiments and supervised assays performed by J.H.S., H.W., Y.X., S.P., H.H.C., C.-H.S., E.W., Z.Z., C.T., C.G., G.V.T., E.F-M., G.Y., Y.Q., P.C.C., Y.C.H., K.O., and R.Z.; L.P. contributed to some experiments, performed transcriptomic analysis of human cancer patient data sets from Oncomine as well as Gene Expression Omnibus using Nexus Expression 2.0 and gene set enrichment analysis; H.W. performed immunohistochemical analyses; T.S. and H.H.C. performed gel filtration; S,C.Y. and S.L.H.were the investigators who coordinated the project; J.C. and M.H.L. designed the research project and drafted the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Sai-Ching Jim Yeung or Mong-Hong Lee.

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https://doi.org/10.1038/ncomms6384

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