CSN6 drives carcinogenesis by positively regulating Myc stability

Abstract

Summary Cullin-RING ubiquitin ligases (CRL) 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 signaling axis and that CSN6 is a positive regulator of Myc. CSN6 enhanced neddylation of Cullin-1 and facilitated auto-ubiquitination/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.

Regulating the stability and localization of CDK inhibitor p27Kip1 via CSN6-COP1 axis

“…CSN6 associates with p27 and increases p27 turnover rate We previously show that CSN6 C/¡ MEF has elevated p27 when compared with wt CSN6 C/C MEFs, 11 we thus hypothesized that CSN6 and p27 have an interactive or regulatory relationship. Co-immunoprecipitation experiments showed endogenous interaction of the 2 proteins in cells (Fig.…”

“…5,[8][9][10][11] The role of the CSN's subunits in cancer has not been well characterized. We previously showed that Csn6¡/¡ mice developed until 7.5 d post-coitus.…”

Circadian Clock Gene CRY2 Degradation Is Involved in Chemoresistance of Colorectal Cancer

“…SCF FBXW7 is known to degrade several proto-oncogenes that function in cellular growth and division pathways, including cyclin E (30), Aurora B (31), Aurora A(32), MYC(33) (34), JUN(35) (36) and Notch (37). Loss-of-function of tumor suppressor FBXW7 increased pro-survival protein MCL1 levels and conferred resistance to Taxol-induced cell death, which indicated that FBXW7 is also involved in drug resistance (38).…”

CSN6 positively regulates c-Jun in a MEKK1-dependent manner

“…Our data show that N-terminal CSN6 alone is not able to mediate MEKK1 downregulation, while fulllength CSN6 can destabilize MEKK1. This is somewhat of a surprise as CSN6's MPN domain is the major domain involved in targeting protein stability regulation such as Myc 31 . The data suggest that every domain of CSN6 is participated in MEKK1 downregulation, which warrants further investigation.…”

“…In addition, we previously observed that CSN6 can regulate the stability of several E3 ligases 15,23,31,32 . On the basis of these findings, we determined whether CSN6 regulates MEKK1 to stabilize c-Jun proteins.…”