Steroidogenic enzymes are essential for prostate cancer development. Enzymes inactivating potent androgens were not investigated thoroughly, which leads to limited interference strategies for prostate cancer therapy. Here we characterized the clinical relevance, significance, and regulation mechanism of enzyme HSD17B2 in prostate cancer development.

HSD17B2 expression was detected with patient specimens and prostate cancer cell lines. Function of HSD17B2 in steroidogenesis, androgen receptor (AR) signaling, and tumor growth was investigated with prostate cancer cell lines and a xenograft model. DNA methylation and mRNA alternative splicing were investigated to unveil the mechanisms of HSD17B2 regulation.

HSD17B2 expression was reduced as prostate cancer progressed. 17βHSD2 decreased potent androgen production by converting testosterone (T) or dihydrotestosterone (DHT) to each of their upstream precursors. HSD17B2 overexpression suppressed androgen-induced cell proliferation and xenograft growth. Multiple mechanisms were involved in HSD17B2 functional silencing including DNA methylation and mRNA alternative splicing. DNA methylation decreased the HSD17B2 mRNA level. Two new catalytic-deficient isoforms, generated by alternative splicing, bound to wild-type 17βHSD2 and promoted its degradation. Splicing factors SRSF1 and SRSF5 participated in the generation of new isoforms.

Our findings provide evidence of the clinical relevance, significance, and regulation of HSD17B2 in prostate cancer progression, which might provide new strategies for clinical management by targeting the functional silencing mechanisms of HSD17B2.

See related commentary by Mostaghel, p. 1139