Cellular levels of key regulatory proteins are controlled via ubiquitination and subsequent degradation. Deubiquitinating enzymes or isopeptidases can potentially prevent targeted destruction of protein substrates through deubiquitination prior to proteasomal degradation. However, only one deubiquitinating enzyme to date has been matched to a specific substrate in mammalian cells and shown to functionally modify it. Here we show that the isopeptidase USP2a (ubiquitin-specific protease-2a) interacts with and stabilizes fatty acid synthase (FAS), which is often overexpressed in biologically aggressive human tumors. Further, USP2a is androgen-regulated and overexpressed in prostate cancer, and its functional inactivation results in decreased FAS protein and enhanced apoptosis. Thus, the isopeptidase USP2a plays a critical role in prostate cancer cell survival through FAS stabilization and represents a therapeutic target in prostate cancer.
Atypical teratoid/rhabdoid tumors (AT/RTs) are highly aggressive brain tumors of early childhood poorly responding to therapy. The majority of cases show inactivation of SMARCB1 (INI1, hSNF5, BAF47), a core member of the adenosine triphosphate (ATP)-dependent SWI/SNF chromatin-remodeling complex. We here report the case of a supratentorial AT/RT in a 9-month-old boy, which showed retained SMARCB1 staining on immunohistochemistry and lacked genetic alterations of SMARCB1. Instead, the tumor showed loss of protein expression of another SWI/SNF chromatin-remodeling complex member, the ATPase subunit SMARCA4 (BRG1) due to a homozygous SMARCA4 mutation [c.2032C>T (p.Q678X)]. Our findings highlight the role of SMARCA4 in the pathogenesis of SMARCB1-positive AT/RT and the usefulness of antibodies directed against SMARCA4 in this diagnostic setting.
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