Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma

Abstract

ETS transcription factors are commonly deregulated in cancer by chromosomal translocation, overexpression or post-translational modification to induce gene expression programs essential in tumorigenicity. Targeted destruction of these proteins may have therapeutic impact. Here we report that Ets-1 destruction is regulated by the deubiquitinating enzyme, Usp9x, and has major impact on the tumorigenic program of metastatic melanoma. Ets-1 deubiquitination blocks its proteasomal destruction and enhances tumorigenicity, which could be reversed by Usp9x knockdown or inhibition. Usp9x and Ets-1 levels are coincidently elevated in melanoma with highest levels detected in metastatic tumours versus normal skin or benign skin lesions. Notably, Ets-1 is induced by BRAF or MEK kinase inhibition, resulting in increased NRAS expression, which could be blocked by inactivation of Usp9x and therapeutic combination of Usp9x and MEK inhibitor fully suppressed melanoma growth. Thus, Usp9x modulates the Ets-1/NRAS regulatory network and may have biologic and therapeutic implications.

Deubiquitinase ubiquitin‐specific protease 9X regulates the stability and function of E3 ubiquitin ligase ring finger protein 115 in breast cancer cells

“…19,36,37 For example, elevated expression of USP9X has been documented in several types of human cancers, including non-small-cell lung cancer, esophageal squamous cell carcinoma, B-cell lymphoma, cervical carcinoma, and melanoma, and its high expression is closely linked with tumor growth, invasion, metastasis, and chemoresistance. 26,36,[38][39][40][41][42][43] Conversely, USP9X has tumor suppressor functions in pancreatic ductal adenocarcinoma 37,44,45 and colorectal cancer. 46 Interestingly, 2 recent studies showed that USP9X stabilizes large tumor suppressor kinase 2, an upstream component of the Hippo pathway, to negatively regulate YAP and its target genes to suppress tumor growth in pancreatic 44,45 and breast 44 cancer.…”

USP9X stabilizes BRCA1 and confers resistance to DNA‐damaging agents in human cancer cells

“…Ubiquitin‐specific peptidase 9X (USP9X) is a highly conserved DUB belonging to the ubiquitin‐specific protease (USP) family . Accumulating evidence shows that USP9X is frequently upregulated and promotes tumorigenesis and chemoresistance in some types of human cancer, such as breast and lung cancer, melanoma, lymphoma, and glioblastoma . Strikingly, a tumor suppressor role of USP9X has been documented in pancreatic, colorectal, and renal cancer .…”

Targeting USP9x/SOX2 axis contributes to the anti-osteosarcoma effect of neogambogic acid

“…can play a dual role in cancers, promoting or suppressing tumor development, depending on the cancer type and disease model studied. For example, by stabilizing MCL1, USP9x can promote cancer cell survival or confer radioresistance in B-cell acute lymphoblastic leukemia (Zhou et al, 2015), non-small-cell lung cancer (Yan et al, 2014) breast and melanoma (Potu et al, 2017a). However, in pancreatic ductal adenocarcinoma, loss of USP9x enhances transformation and protects pancreatic cancer cells from apoptosis (Perez-Mancera et al, 2012).…”