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

Bone and soft tissue tumors 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, in aneurysmal bone cysts and the related benign lesion nodular fasciitis (NF). Ectopic expression of USP6 is known to drive formation of tumors which recapitulate key features of ABC and NF, 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 tumor formation. We found that USP6 directly de-ubiquitinated 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 NF 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 oncogenically activated USP6.