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 Hollenhorst, Ugur Eskiocak, Moshe Talpaz, Nicholas J. Donato

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number14449
JournalNature Communications
Volume8
DOIs
StatePublished - Feb 15 2017

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Ubiquitination
destruction
Melanoma
Skin
Proto-Oncogene Proteins B-raf
MAP Kinase Kinase Kinases
Mitogen-Activated Protein Kinase Kinases
Gene expression
Tumors
Genetic Translocation
Transcription Factors
gene expression
Post Translational Protein Processing
deactivation
lesions
inhibitors
enzymes
Neoplasms
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Potu, H., Peterson, L. F., Kandarpa, M., Pal, A., Sun, H., Durham, A., ... Donato, N. J. (2017). Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma. Nature Communications, 8, [14449]. https://doi.org/10.1038/ncomms14449

Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma. / Potu, Harish; Peterson, Luke F.; Kandarpa, Malathi; Pal, Anupama; Sun, Hanshi; Durham, Alison; Harms, Paul W.; Hollenhorst, Peter; Eskiocak, Ugur; Talpaz, Moshe; Donato, Nicholas J.

In: Nature Communications, Vol. 8, 14449, 15.02.2017.

Research output: Contribution to journalArticle

Potu, H, Peterson, LF, Kandarpa, M, Pal, A, Sun, H, Durham, A, Harms, PW, Hollenhorst, P, Eskiocak, U, Talpaz, M & Donato, NJ 2017, 'Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma', Nature Communications, vol. 8, 14449. https://doi.org/10.1038/ncomms14449
Potu, Harish ; Peterson, Luke F. ; Kandarpa, Malathi ; Pal, Anupama ; Sun, Hanshi ; Durham, Alison ; Harms, Paul W. ; Hollenhorst, Peter ; Eskiocak, Ugur ; Talpaz, Moshe ; Donato, Nicholas J. / Usp9x regulates Ets-1 ubiquitination and stability to control NRAS expression and tumorigenicity in melanoma. In: Nature Communications. 2017 ; Vol. 8.
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