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Updated: Sep 27, 2025
Murine Prostate Micro-dissection and Surgical Castration
Published on: May 11, 2016
A SIX1 degradation inducer blocks excessive proliferation of prostate cancer
Yuning Liao1,2, Wenshuang Sun2, Zhenlong Shao2
1Affiliated Cancer Hospital & institute of Guangzhou Medical University, Guangzhou, Guangdong, 510095, China.
Abstract:
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.
Insights
Researchers identified SNS-032 as a promising drug to target the USP1-SIX1 axis in prostate cancer (PC). This kinase inhibitor induces SIX1 degradation, overcoming castration resistance and promoting cancer cell death.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Prostate cancer (PC) presents significant challenges, particularly castration resistance developed during androgen deprivation therapy.
- Deubiquitinases are emerging as critical therapeutic targets for cancer treatment.
- USP1 (ubiquitin specific peptidase 1) deubiquitinates SIX1 (sine oculis homeobox homolog 1), promoting PC proliferation and castration resistance, partly via GRP75.
Purpose of the Study:
- To identify a SIX1 degradation inducer by inhibiting the USP1-SIX1 axis.
- To evaluate the efficacy of identified compounds in prostate cancer models.
Main Methods:
- Screening of kinase inhibitors to find agents triggering SIX1 ubiquitinated degradation.
- Assessing the effects of the identified inhibitor (SNS-032) on USP1-SIX1 axis activity, cell cycle progression, and apoptosis in PC cells.
- Evaluating the synergistic effects of SNS-032 combined with enzalutamide in AR-V7 highly expressing 22Rv1 cells.
Main Results:
- SNS-032 was identified as the most effective kinase inhibitor for inducing SIX1 ubiquitinated degradation.
- SNS-032 inhibited the USP1-SIX1 axis, suppressed cell cycle progression, and induced apoptosis in PC cells.
- Combination therapy with SNS-032 and enzalutamide synergistically enhanced apoptosis and downregulated USP1, SIX1, and AR/AR-V7 in 22Rv1 cells.
Conclusions:
- SNS-032 effectively targets the USP1-SIX1 axis, leading to SIX1 degradation and PC cell death.
- This study presents a novel strategy for overcoming castration resistance in prostate cancer.
- Targeting the USP1-SIX1 axis with SIX1 degradation inducers offers a potential therapeutic approach for advanced prostate cancer.
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