title: Hydrogen sulfide represses androgen receptor transactivation by targeting at the second zinc finger module.
abstract: Androgen receptor (AR) signaling is indispensable for the development of prostate cancer from the initial androgen-dependent state to a later aggressive androgen-resistant state. This study examined the role of hydrogen sulfide (H(2)S), a novel gasotransmitter, in the regulation of AR signaling as well as its mediation in androgen-independent cell growth in prostate cancer cells. Here we found that H(2)S inhibits cell proliferation of both androgen-dependent (LNCaP) and antiandrogen-resistant prostate cancer cells (LNCaP-B), with more significance on the latter, which was established by long term treatment of parental LNCaP cells with bicalutamide. The expression of cystathionine γ-lyase (CSE), a major H(2)S producing enzyme in prostate tissue, was reduced in both human prostate cancer tissues and LNCaP-B cells. LNCaP-B cells were resistant to bicalutamide-induced cell growth inhibition, and CSE overexpression could rebuild the sensitivity of LNCaP-B cells to bicalutamide. H(2)S significantly repressed the expression of prostate-specific antigen (PSA) and TMPRSS2, two AR-targeted genes. In addition, H(2)S inhibited AR binding with PSA promoter and androgen-responsive element (ARE) luciferase activity. We further found that AR is post-translationally modified by H(2)S through S-sulfhydration. Mutation of cysteine 611 and cysteine 614 in the second zinc finger module of AR-DNA binding domain diminished the effects of H(2)S on AR S-sulfhydration and AR dimerization. These data suggest that reduced CSE/H2S signaling contributes to antiandrogen-resistant status, and sufficient level of H(2)S is able to inhibit AR transactivation and treat castration-resistant prostate cancer.
authors.forename: Kexin
authors.initials: K
authors.lastname: Zhao
authors.forename: Shuangshuang
authors.initials: S
authors.lastname: Li
authors.forename: Lingyun
authors.initials: L
authors.lastname: Wu
authors.forename: Christopher
authors.initials: C
authors.lastname: Lai
authors.forename: Guangdong
authors.initials: G
authors.lastname: Yang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D064426:Gasotransmitters / Q000494:pharmacology*; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D007610:Kallikreins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017430:Prostate-Specific Antigen / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy; D055503:Protein Multimerization / Q000187:drug effects / Q000235:genetics; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects* / Q000235:genetics; D016335:Zinc Fingers
chemical_list: D064426:Gasotransmitters; D009363:Neoplasm Proteins; D011944:Receptors, Androgen; C549870:KLK3 protein, human; D007610:Kallikreins; D012697:Serine Endopeptidases; C421305:TMPRSS2 protein, human; C000588699:TMPRSS2 protein, mouse; D017430:Prostate-Specific Antigen; D006862:Hydrogen Sulfide