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

Harish Potu, Luke F. Peterson, Malathi Kandarpa, Anupama Pal, Hanshi Sun, Alison Durham, Paul W. Harms, Peter C. Hollenhorst, Ugur Eskiocak, Moshe Talpaz and Nicholas J. Donato ()
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Harish Potu: University of Michigan School of Medicine and Comprehensive Cancer Center
Luke F. Peterson: University of Michigan School of Medicine and Comprehensive Cancer Center
Malathi Kandarpa: University of Michigan School of Medicine and Comprehensive Cancer Center
Anupama Pal: University of Michigan School of Medicine and Comprehensive Cancer Center
Hanshi Sun: University of Michigan School of Dentistry
Alison Durham: University of Michigan School of Medicine
Paul W. Harms: University of Michigan School of Medicine
Peter C. Hollenhorst: Medical Sciences Program, Indiana University Bloomington
Ugur Eskiocak: Howard Hughes Medical Institute, University of Texas Southwestern Medical Center
Moshe Talpaz: University of Michigan School of Medicine and Comprehensive Cancer Center
Nicholas J. Donato: University of Michigan School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14449

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