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Τρίτη 18 Σεπτεμβρίου 2018

Functional silencing of HSD17B2 in prostate cancer promotes disease progression

Purpose: Steroidogenic enzymes are essential for prostate cancer development. Enzymes inactivating potent androgens were not investigated thoroughly, which leads to limited interfere strategies for prostate cancer therapy. Here we characterized the clinical relevance, significance and regulation mechanism of enzyme HSD17B2 in prostate cancer development. Experimental Design: HSD17B2 expression was detected with patient specimens and prostate cancer cell lines. Function of HSD17B2 in steroidogenesis, AR signaling and tumor growth was investigated with prostate cancer cell lines and xenograft model. DNA methylation and mRNA alternative splicing were investigated to unveil the mechanisms of HSD17B2 regulation. Results: HSD17B2 expression was reduced as prostate cancer progresses. 17βHSD2 decreased potent androgen production by converting testosterone (T) or dihydrotestosterone (DHT) to their upstream precursors. HSD17B2 overexpression suppressed androgen-induced cell proliferation and xenograft growth. Multiple mechanisms were involved in HSD17B2 functional silencing including DNA methylation, androgen stimulation and mRNA alternative splicing. DNA methylation and T stimulation decreased HSD17B2 mRNA or protein level respectively. 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. Conclusion: 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.



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