Dataset Information

Jak1-STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis.

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 USP6'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. Cancer Res; 76(18); 5337-47. ©2016 AACR.

SUBMITTER: Quick L

PROVIDER: S-EPMC5026615 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Jak1-STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis.

Quick Laura L Young Robert R Henrich Ian C IC Wang Xiaoke X Asmann Yan W YW Oliveira Andre M AM Chou Margaret M MM

Cancer research 20160720 18

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; howev ...[more]

PMID: 27440725

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Project description:Since the time of Rudolf Virchow in the 19th century, it has been well-known that cancer-associated inflammation contributes to tumor initiation and progression. However, it remains unclear whether a collapse of the balance between the antitumor immune response via the immunological surveillance system and protumor immunity due to cancer-related inflammation is responsible for cancer malignancy. The majority of inflammatory signals affect tumorigenesis by activating signal transducer and activation of transcription 3 (STAT3) and nuclear factor-κB. Persistent STAT3 activation in malignant cancer cells mediates extremely widespread functions, including cell growth, survival, angiogenesis, and invasion and contributes to an increase in inflammation-associated tumorigenesis. In addition, intracellular STAT3 activation in immune cells causes suppressive effects on antitumor immunity and leads to the differentiation and mobilization of immature myeloid-derived cells and tumor-associated macrophages. In many cancer types, STAT3 does not directly rely on its activation by oncogenic mutations but has important oncogenic and malignant transformation-associated functions in both cancer and stromal cells in the tumor microenvironment (TME). We have reported a series of studies aiming towards understanding the molecular mechanisms underlying the proliferation of various types of tumors involving signal-transducing adaptor protein-2 as an adaptor molecule that modulates STAT3 activity, and we recently found that AT-rich interactive domain-containing protein 5a functions as an mRNA stabilizer that orchestrates an immunosuppressive TME in malignant mesenchymal tumors. In this review, we summarize recent advances in our understanding of the functional role of STAT3 in tumor progression and introduce novel molecular mechanisms of cancer development and malignant transformation involving STAT3 activation that we have identified to date. Finally, we discuss potential therapeutic strategies for cancer that target the signaling pathway to augment STAT3 activity.

Dataset Information

Jak1-STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis.

Publications

Jak1-STAT3 Signals Are Essential Effectors of the USP6/TRE17 Oncogene in Tumorigenesis.

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