The Hippo pathway has been identified as a key barrier for
tumorigenesis, acting through downregulation of YAP/TAZ activity. Elevated YAP/TAZ activity has been documented in many human
cancers. Ubiquitylation has been shown to play a key role in regulating YAP/TAZ activity through downregulation of a number of Hippo pathway components. Several
ubiquitin ligase complexes have been implicated in this process, however, little is known about the deubiquitylating
enzymes that counteract these activities to regulate YAP/TAZ. Here we identify the deubiquitylating
enzyme USP9x as a regulator of YAP/TAZ activity. We demonstrate that USPx regulates
ubiquitin-mediated turnover of the YAP inhibitor,
Angiomotin. USP9x acts to deubiquitylate
Angiomotin at
lysine 496, resulting in stabilization of
Angiomotin and lower YAP/TAZ activity. USP9x
mRNA levels were reduced in several
cancers. Clinically, USP9x
mRNA levels were reduced in several
cancers with low USPx expression correlating with poor prognosis in renal clear cell
carcinoma. Our data indicate that USP9x may be a useful
biomarker for renal clear cell
carcinoma.