title: SUMO-specific protease 1 modulates cadmium-augmented transcriptional activity of androgen receptor (AR) by reversing AR SUMOylation.
abstract: Cadmium is a potential prostate carcinogen and can mimic the effects of androgen by a mechanism that involves the hormone-binding domain of the androgen receptor (AR), which is a key transcriptional factor in prostate carcinogenesis. We focused on transcriptional activity of AR to investigate the toxicity of cadmium exposure on human prostate cell lines. Cadmium increased the proliferative index of LNCaP and the proliferative effect was obstructed significantly by AR blocking agent. In luciferase assay, cadmium activated the transcriptional activity of AR in 293T cells co-transfected with wild-type AR and an ARE (AR response elements)-luciferase reporter gene. Cadmium also increased expression of PSA, a downstream gene of AR, whereas the metal had no significant effect on AR amount. AR is regulated by multiple posttranslational modifications including SUMOylation. SUMOylated AR shows a lower transcriptional activity. SUMO-specific protease 1 (SENP1) decreases AR SUMOylation by deconjugating AR-SUMO covalent bond. We detected that cadmium increased the amount of SENP1 in a dose and time dependent manner. Knocking down of SENP1 by RNAi led to decrease of PSA expression and transcriptional activity of AR in luciferase assay. Furthermore, co-immunoprecipitation (Co-IP) results showed that SUMOylation level of AR was decreased after cadmium treatment. In conclusion, our results indicated that cadmium-induced SENP1 enhanced AR transcriptional activity by decreasing AR SUMOylation.
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.
authors.forename: Ruiqin
authors.initials: R
authors.lastname: Wu
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China; College of Life Science, Lanzhou University, Lanzhou, Gansu 730000, China.
authors.forename: Yaxiong
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Yuan
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.
authors.forename: Yimei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.
authors.forename: Jun
authors.initials: J
authors.lastname: He
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Evaluation and Research Centre for Toxicology, Institute of Disease Control and Prevention, Academy of Military Medical Sciences, Beijing 100071, China. Electronic address: pengsq@hotmail.com.
authors.forename: Shuangqing
authors.initials: S
authors.lastname: Peng
mesh_terms: D002104:Cadmium / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism / Q000502:physiology*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000187:drug effects*; D058207:Sumoylation / Q000187:drug effects*; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D011944:Receptors, Androgen; D002104:Cadmium; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases
keywords: Androgen receptor; Cadmium; Prostate cancer; SENP1; SUMOylation; Transcriptional activity