Jak1-STAT3 signals are essential effectors of the USP6/TRE17 oncogene in tumorigenesis

Laura Quick, Robert Young, Ian C. Henrich, Xiaoke Wang, Yan W. Asmann, Andre M. Oliveira, Margaret M. Chou

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Bone and soft tissue tumors (BSTT) are relatively poorly understood, hampering the development of effective therapies. Here we report a role for the ubiquitin-specific protease 6 (USP6)/TRE17 oncogene, which is overexpressed upon chromosome translocation in various human tumors, including aneurysmal bone cyst (ABC), and the related benign lesion nodular fasciitis. Ectopic expression of USP6 is known to drive formation of tumors, which recapitulate key features of ABC and nodular fasciitis; however, the identity of USP60 s relevant substrates has been obscure. Here we report that the Jak1-STAT3 signaling pathway serves as an essential effector of USP6 in BSTT formation. We found that USP6 directly deubiquitinated Jak1, leading to its stabilization and activation of STAT3. The tumorigenic potential of USP6 was attenuated significantly by CRISPR-mediated deletion of Jak1 or STAT3, or by administration of a Jak family inhibitor. Analysis of primary clinical samples of nodular fasciitis confirmed the activation of a Jak1-STAT3 gene signature in vivo. Together, our studies highlight Jak1 as the first identified substrate for USP6, and they offer a mechanistic rationale for the clinical investigation of Jak and STAT3 inhibitors as therapeutics for the treatment of bone and soft tissue tumors along with other neoplasms driven by USP6 overexpression.

Original languageEnglish (US)
Pages (from-to)5337-5347
Number of pages11
JournalCancer research
Volume76
Issue number18
DOIs
StatePublished - Sep 15 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Quick, L., Young, R., Henrich, I. C., Wang, X., Asmann, Y. W., Oliveira, A. M., & Chou, M. M. (2016). Jak1-STAT3 signals are essential effectors of the USP6/TRE17 oncogene in tumorigenesis. Cancer research, 76(18), 5337-5347. https://doi.org/10.1158/0008-5472.CAN-15-2391