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; Nicholas J Donato

doi:10.1038/ncomms14449

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

Nat Commun. 2017 Feb 15:8:14449. doi: 10.1038/ncomms14449.

Authors

Affiliations

¹ Department of Internal Medicine/Division of Hematology/Oncology, University of Michigan School of Medicine and Comprehensive Cancer Center, Ann Arbor, Michigan 48109, USA.
² Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan 48109, USA.
³ Department of Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
⁴ Departments of Pathology and Dermatology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
⁵ Department of Biochemistry and Molecular Biology, Medical Sciences Program, Indiana University Bloomington, 1001 Third St, Bloomington, Indiana 47405, USA.
⁶ Children's Research Institute and Department of Pediatrics, Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
⁷ Department of Pharmacology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinogenesis / drug effects
Carcinogenesis / genetics
Carcinogenesis / pathology*
Cell Line, Tumor
Cell Proliferation / drug effects
GTP Phosphohydrolases / genetics*
GTP Phosphohydrolases / metabolism
Gene Expression Regulation, Neoplastic*
HEK293 Cells
Humans
Melanoma / drug therapy
Melanoma / genetics*
Melanoma / pathology*
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Mice
Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
Mitogen-Activated Protein Kinase Kinases / metabolism
Promoter Regions, Genetic / genetics
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Protein Stability
Proteolysis / drug effects
Proto-Oncogene Protein c-ets-1 / metabolism*
Proto-Oncogene Proteins B-raf / antagonists & inhibitors
Proto-Oncogene Proteins B-raf / metabolism
Ubiquitin Thiolesterase / metabolism*
Ubiquitination*

Substances

ETS1 protein, human
Membrane Proteins
Protein Kinase Inhibitors
Proto-Oncogene Protein c-ets-1
USP9X protein, human
Proto-Oncogene Proteins B-raf
Mitogen-Activated Protein Kinase Kinases
Ubiquitin Thiolesterase
GTP Phosphohydrolases
NRAS protein, human