Dataset Information

CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9.

ABSTRACT: As a critical subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), CSN6 is upregulated in some human cancers and plays critical roles in tumorigenesis and progression, but its biological functions and molecular mechanisms in melanoma remain unknown. Our study showed that CSN6 expression was upregulated in melanoma patients and cells, and correlated with poor survival in melanoma patients. In melanoma cells, CSN6 knockdown remarkably inhibited cell proliferation, tumorigenicity, migration, and invasion, whereas CSN6 recovery rescued the proliferative and metastatic abilities. Notably, we identified that CSN6 stabilized CDK9 expression by reducing CDK9 ubiquitination levels, thereby activating CDK9-mediated signaling pathways. In addition, our study described a novel CSN6-interacting E3 ligase UBR5, which was negatively regulated by CSN6 and could regulate the ubiquitination and degradation of CDK9 in melanoma cells. Furthermore, in CSN6-knockdown melanoma cells, UBR5 knockdown abrogated the effects caused by CSN6 silencing, suggesting that CSN6 activates the UBR5/CDK9 pathway to promote melanoma cell proliferation and metastasis. Thus, this study illustrates the mechanism by which the CSN6-UBR5-CDK9 axis promotes melanoma development, and demonstrate that CSN6 may be a potential biomarker and anticancer target in melanoma.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC7822921 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9.

Zhang Yanli Y Hou Jianbing J Shi Shaomin S Du Juan J Liu Yudong Y Huang Pan P Li Qian Q Liu Lichao L Hu Huanrong H Ji Yacong Y Guo Leiyang L Shi Yaqiong Y Liu Yaling Y Cui Hongjuan H

Cell death & disease 20210122 1

As a critical subunit of the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), CSN6 is upregulated in some human cancers and plays critical roles in tumorigenesis and progression, but its biological functions and molecular mechanisms in melanoma remain unknown. Our study showed that CSN6 expression was upregulated in melanoma patients and cells, and correlated with poor survival in melanoma patients. In melanoma cells, CSN6 knockdown remarkably inhibited cell proliferation, tumorigenic ...[more]

PMID: 33483464

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Project description:BackgroundUbiquitination is a basic post-translational modification for cellular homeostasis, and members of the conjugating enzyme (E2) family are the key components of the ubiquitin-proteasome system. However, the role of E2 family in colorectal cancer (CRC) is largely unknown. Our study aimed to investigate the role of Ube2v1, one of the ubiquitin-conjugating E2 enzyme variant proteins (Ube2v) but without the conserved cysteine residue required for the catalytic activity of E2s, in CRC.MethodsImmunohistochemistry and real-time RT-PCR were used to study the expressions of Ube2v1 at protein and mRNA levels in CRC, respectively. Western blotting and immunofluorescence, transmission electron microscopy, and in vivo rescue experiments were used to study the functional effects of Ube2v1 on autophagy and EMT program. Quantitative mass spectrometry, immunoprecipitation, ubiquitination assay, western blotting, and real-time RT-PCR were used to analyze the effects of Ube2v1 on histone H4 lysine 16 acetylation, interaction with Sirt1, ubiquitination of Sirt1, and autophagy-related gene expression.ResultsUbe2v1 was elevated in CRC samples, and its increased expression was correlated with poorer survival of CRC patients. Ube2v1 promoted migration and invasion of CRC cells in vitro and tumor growth and metastasis of CRC cells in vivo. Interestingly, Ube2v1suppressed autophagy program and promoted epithelial mesenchymal transition (EMT) and metastasis of CRC cells in an autophagy-dependent pattern in vitro and in vivo. Moreover, both rapamycin and trehalose attenuated the enhanced Ube2v1-mediated lung metastasis by inducing the autophagy pathway in an orthotropic mouse xenograft model of lung metastasis. Mechanistically, Ube2v1 promoted Ubc13-mediated ubiquitination and degradation of Sirt1 and inhibited histone H4 lysine 16 acetylation, and finally epigenetically suppressed autophagy gene expression in CRC.ConclusionsOur study functionally links Ube2v1, an E2 member in the ubiquitin-proteasome system, to autophagy program, thereby shedding light on developing Ube2v1 targeted therapy for CRC patients.

Dataset Information

CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9.

Publications

CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9.

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