Ubiquitin carboxyl-terminal hydrolase 12 and Ubiquitin carboxyl-terminal hydrolase 46 (USP12/USP46)

Ubiquitin carboxyl-terminal hydrolase 12 (USP12) and 46 (USP46) are closely related deubiquitinating enzymes (DUBs) belonging to the ubiquitin-specific protease family [1, 4]. They are highly homologous (approximately 90% sequence identity) and typically function within a ternary complex with the WD40-repeat proteins WDR48 (UAF1) and WDR20, which are essential for their maximal catalytic activity [6, 9]. These enzymes regulate cellular homeostasis by removing ubiquitin from specific substrates, thereby preventing their proteasomal or lysosomal degradation [2, 5]. Key substrates include the androgen receptor (AR), histones H2A and H2B, Akt phosphatases (PHLPP1/2), and various cell surface receptors such as integrins and AMPA receptors [6, 8, 10, 12]. In clinical contexts, USP12 and USP46 are significant therapeutic targets due to their roles in oncology and neurology [1, 4]. They are frequently overexpressed in cancers like prostate and breast cancer, where they stabilize oncogenic drivers such as AR, promoting tumor growth and survival [1, 8]. Conversely, they can act as tumor suppressors in other tissues, such as colon cancer, by stabilizing phosphatases that downregulate the Akt signaling pathway [12]. Beyond cancer, these enzymes are implicated in neurodegenerative diseases like Huntington's disease and neurological conditions affecting mood and memory [1, 10, 11]. Small molecule inhibitors, most notably Galeterone and its derivatives, have been shown to target USP12/46, offering a potential strategy for treating hormone-refractory cancers and other disorders driven by DUB dysregulation [1, 4].

Other names

Ubiquitin-specific protease 12Ubiquitin-specific protease 46USP12USP46Deubiquitinating enzyme 12Deubiquitinating enzyme 46Ubiquitin thioesterase 12Ubiquitin thioesterase 46

Inhibition of the deubiquitinating activity of the USP12/46-WDR48-WDR20 complex, leading to the proteasomal or lysosomal degradation of stabilized substrates such as the androgen receptor (AR) or the accumulation of ubiquitinated proteins [1, 4, 8].