Prostate cancer (PC) remains a great medical challenge due to its high incidence and the development of
castration resistance in patients treated with
androgen deprivation
therapy.
Deubiquitinases, the
enzymes that specifically hydrolyze
ubiquitin chains on their substrates, were recently proposed as a serious of critical therapeutic targets for
cancer treatment. Our previous study has been reported that the
ubiquitin specific peptidase 1 (USP1) functionally acts as a
deubiquitinase of sine oculis homeobox homolog 1 (SIX1) and contributes to the proliferation and
castration resistance of PC. The stabilization of SIX1 by USP1 partially depends on the status of
glucose-regulated
protein 75 (
GRP75). In this study, we aimed to identify a SIX1 degradation inducer via inhibiting the USP1-SIX1 axis. we screened a range of
kinase inhibitors and showed that
SNS-032 is the best candidate to trigger the ubiquitinated degradation of SIX1.
SNS-032 not only restrains activity of the USP1-SIX1 axis and cell cycle progression, but also results in apoptosis of PC cells. Moreover, the combination of
SNS-032 and
enzalutamide synergistically induces apoptosis and downregulates expression of USP1, SIX1, and AR/AR-V7 in AR-V7 highly expressed 22Rv1 cells. Overall, our findings may develop a novel and effective strategy to overcome
castration resistance in PC for the identification of a SIX1 degradation inducer via targeting the USP1-SIX1 axis.