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

Yanli Zhang,Lichao Liu,Jianbing Hou,Pan Huang,Shaomin Shi,Qian Li,Yudong Liu,Juan Du,Yaling Liu,Hongjuan Cui,Huanrong Hu,Leiyang Guo,Yacong Ji,Yaqiong Shi

doi:10.1038/s41419-021-03398-0

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.

Highlights

Malignant melanoma (MM) is becoming the most lethal type of cutaneous carcinoma because of its rapid progression, tendency to metastasize and poor clinical prognosis
To further determine whether the expression of CSN6 is associated with the prognosis of melanoma patients, survival database analysis of the R2: Genomics Analysis and Visualization Platform was performed and found that high expression of CSN6 was associated with poor overall survival, whereas a low CSN6 level was implicated in prolonged overall survival (Fig. 1E, F)
To further confirm the involvement of CSN6 in melanoma proliferation and metastasis, CSN6 expression was recovered through transfection of a full-length CSN6 sequence resistant to short hairpin RNA (shRNA)#1 targeting into CSN6-knockdown melanoma cells, and the results showed that CSN6 protein and messenger RNA expression levels were successfully recovered (Fig. 3A)

Summary

Introduction

Malignant melanoma (MM) is becoming the most lethal type of cutaneous carcinoma because of its rapid progression, tendency to metastasize and poor clinical prognosis. Cutaneous melanoma accounts for approximately 232,100 newly diagnosed primary malignant tumors (1.7% of all cases) and approximately 55,500 cancer deaths (0.7% of all death) per year[1]. The constitutive photomorphogenic 9 (COP9) signalosome (CSN) complex is highly evolutionarily conserved and ubiquitous in all eukaryotes. It consists of nine subunits, including CSN1-CSN8 and the newly discovered. Zhang et al Cell Death and Disease (2021)12:118 subunit CSN acidic protein (CSNAP)[5], and the CSN signaling complex is involved in protein degradation[6,7,8], signal transduction[9,10,11,12,13], the DNA damage response[8,14,15], transcriptional activation[16], and tumorigenesis[8,12,17,18]. CSN6 increases the stability of β-catenin by preventing its ubiquitination and degradation, interacts with p27 and increases its degradation, and stabilizes COP1 by reducing COP1 autoubiquitination to mediate 14-3-3σ ubiquitination[6,11,14]

Methods

Results

Conclusion