Abstract
Elevated subcutaneous adipose tissue in obese men correlates strongly with a higher risk of aggressive prostate cancer and poor treatment outcomes, but the exact mechanism underlying the increased risk remains elusive. To address this question, we analyzed prostate cancer transcriptomic data from The Cancer Genome Atlas as well as single-cell RNA sequencing and tissue microarray data from prostate cancer cells. Subcutaneous adipose tissue-associated cysteine-rich protein 2 (CSRP2) was significantly downregulated in prostate cancer epithelial cells. Knockdown of CSRP2 promoted proliferation of prostate cancer cell lines DU145 and PC3, whereas the opposite effect was observed with CSRP2 overexpression. In vivo xenograft assays confirmed that CSRP2 overexpression inhibits the growth of prostate cancer cells. Importantly, co-immunoprecipitation and mass spectrometry assays confirmed that CSRP2 inhibits the deubiquitination of WD40 repeat protein 5 (WDR5) by ubiquitin-specific protease 44 (USP44). Overexpression of WDR5 reversed the growth inhibition of CSRP2 overexpression on prostate cancer cells. Altogether, our data indicate that CSRP2 suppresses prostate cancer cell proliferation via a CSRP2/WDR5/USP44 dependent pathway to control prostate cancer progression, suggesting a potential mechanism for prostate cancer treatment.