CSN6 drives carcinogenesis by positively regulating Myc stability.
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.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jian
J
Chen
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ji-Hyun
JH
Shin
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ruiying
R
Zhao
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Liem
L
Phan
Department of GI Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Hua
H
Wang
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Yuwen
Y
Xue
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Sean M
SM
Post
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Hyun
H
Ho Choi
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Jiun-Sheng
JS
Chen
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Edward
E
Wang
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Zhongguo
Z
Zhou
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Chieh
C
Tseng
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Christopher
C
Gully
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Guermarie
G
Velazquez-Torres
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Enrique
E
Fuentes-Mattei
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Giselle
G
Yeung
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Yi
Y
Qiao
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Ping-Chieh
PC
Chou
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Chun-Hui
CH
Su
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Yun-Chih
YC
Hsieh
Department of Education and Research, Taichung Veterans General Hospital, No. 160, Section 3, Chung-Gang Road, Taichung, 40705 Taiwan, ROC.
Shih-Lan
SL
Hsu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Kazufumi
K
Ohshiro
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Tattym
T
Shaikenov
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Huamin
H
Wang
1] Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA [2] Department of Emergency Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Sai-Ching Jim
SC
Yeung
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Mong-Hong
MH
Lee
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis / Q000502:physiology*; D000818:Animals; D000075686:COP9 Signalosome Complex; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D055785:Gene Knockdown Techniques; D008223:Lymphoma / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics; D009374:Neoplasms, Experimental / Q000235:genetics; D010447:Peptide Hydrolases / Q000096:biosynthesis / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000502:physiology*; D044843:SKP Cullin F-Box Protein Ligases / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; C000603300:Cops6 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D044843:SKP Cullin F-Box Protein Ligases; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex