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

Abstract

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 USP35high 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.

Ubiquitin-specific Protease 35 Promotes Gastric Cancer Metastasis by Increasing the Stability of Snail1

“…USP35 influences multiple biological functions, such as mitosis, ER stress-induced apoptosis, cisplatin-induced apoptosis, ferroptosis, mevalonate metabolism, cell proliferation, and the STING signaling pathway, by deubiquitinating various target substrates, including Aurora B [30], RRBP1 [31], BIRC3 [32], ferroportin [33], BRPF1 [38], estrogen receptor α [39], and STING [34]. However, the role of USP35 in EMT and tumor metastasis has not yet been reported.…”

Exploiting epigenetic targets to overcome taxane resistance in prostate cancer

“…Moreover, somatic BRPF1 mutations have been identified in sonic hedgehog medulloblastoma [ 57 ] and pediatric cancers [ 58 ]. Although there are not many studies on the function of BRPFs in cancer, its significance has been noted in liver cancer [ 59 ], lower-grade gliomas [ 60 ] and PCa [ 61 ]. Gene ablation or pharmacological inactivation of BRPF1 significantly attenuated HCC cell growth in vitro and in vivo [ 59 ].…”

“…Xia et al identified BRPF1 as a potential drug target in lower-grade gliomas, as inhibiting BRPF1 function or silencing BRPF1 was found to reduce glioma cell proliferation and colony formation [ 60 ]. Lin et al showed the USP35/BRPF1 axis promoted malignant features of PCa by activating the mevalonate pathway [ 61 ]. Although the oncogenic role of BRPF1 was clearly demonstrated in these studies, its relationship with drug resistance has not been questioned.…”

Bromodomain (BrD) Family Members as Regulators of Cancer Stemness—A Comprehensive Review

“…Similarly, Cheng et al [ 91 ] demonstrated that BRPF1 might serve as a druggable target in liver cancer, where BRPF1 was involved in the regulation of cell cycle progression, senescence, and cancer stemness of hepatocellular carcinoma. In prostate tumors, accumulated BRPF1 protein accelerated the cell growth, stem-like properties, and migration of cancer cells, further supporting the role of BRPF1 in cancer stemness [ 92 ]. As for BRPF2 and BRPF3, little is known about their engagement in cancer development and progression, leaving an open question of whether they exert similar activity as BRPF1 in maintaining cancer stem cell-like phenotype.…”