Ubiquitin-specific protease 6 (USP6)

Ubiquitin-specific protease 6 (USP6), also known as TRE17 or Tre-2, is a deubiquitinating enzyme (DUB) that plays a critical role in regulating protein stability and cellular signaling by removing ubiquitin chains from target proteins, thereby preventing their proteasomal degradation [1, 2, 6]. It is primarily recognized for its involvement in various mesenchymal neoplasms, where chromosomal translocations lead to its overexpression under the control of strong promoters, such as CDH11 or MYH9 [5, 7, 17]. These genetic rearrangements are hallmark diagnostic features of diseases like aneurysmal bone cysts and nodular fasciitis [9, 19]. Beyond its oncogenic role, USP6 modulates key pathways including NF-κB, Wnt/β-catenin, and JAK-STAT, which influence cell proliferation, vesicular trafficking, and the inflammatory microenvironment [1, 2, 16]. Interestingly, in specific contexts such as Ewing sarcoma, USP6 may function as a tumor suppressor by enhancing immune activation and chemokine production [15, 16]. Therapeutic targeting of USP6 with small-molecule inhibitors like FT385 and PR-619 is an emerging area of research aimed at disrupting its oncogenic activity in sensitive tumors [1, 3, 4].

Other names

TRE17Tre-2HRP1RN-treUbiquitin carboxyl-terminal hydrolase 6Deubiquitinating enzyme 6Proto-oncogene TRE-2TRESMCRUbiquitin-specific-processing protease 6

Inhibition of deubiquitinating activity to prevent the stabilization of oncogenic proteins and disrupt overactive signaling pathways.