Deubiquitinase USP35 stabilizes BRPF1 to activate mevalonate (MVA) metabolism during prostate tumorigenesis

The mutual interplay between epigenetic modifications and metabolic rewiring contributes to malignant features of prostate adenocarcinoma (PRAD). This study aimed to uncover the biological roles of deubiquitylase USP35 in PRAD and find effective epigenetic or metabolic targets. Bioinformatic tools or methods revealed that USP35 is upregulated in PRAD samples and correlates with inferior prognosis. The in vitro and in vivo assays suggested that USP35 could enhance malignant features of PRAD cells. Mechanistically, we found that USP35 could directly deubiquitinate and stabilize BRPF1 proteins. USP35 depends on accumulated BRPF1 proteins to accelerate cell growth, stem-like properties, and migration in vitro and in vivo. Interestingly, high BRPF1 could bind to promoter of SREBP2 and activate the SREBP2 transcriptional capacity. Therefore, USP35/BRPF1 aixs could promote expressions of mevalonate (MVA) metabolism signature in a SREBP2-dependent manner. USP35 depends on BRPF1 to maintain the activity of mevalonate metabolism in PRAD cells. Last of all, we observed that targeting BRPF1 or using MVA inhibitor (atorvastatin) are effective to suppress USP35^high PRAD in vivo tumor growth. USP35 is an indicator of MVA metabolic signature in PRAD. Collectively, our study highlighted the USP35/BRPF1/SREBP2 axis in modulating MVA metabolism in PRAD, suggesting the significance of BRPF1 or MVA as the potential therapeutic targets for PRAD treatment.