title: SUMOylation of TBL1 and TBLR1 promotes androgen-independent prostate cancer cell growth.
abstract: Chronic inflammation is strongly associated with prostate cancer pathogenesis. Transducin β-like protein (TBL1) and Transducin β-like 1X-linked receptor 1 (TBLR1) have been identified recently as a coactivator for NF-κB-mediated transcription; however, the underlying mechanism by which TBL1 and TBLR1 activate NF-κB function during inflammation remains unknown. Here, we demonstrate that cytokine production is significantly elevated in androgen-independent PC-3 prostate cancer cells compared with androgen-dependent LNCaP prostate cancer cells. Elevated cytokine production positively correlates with the TBL1 and TBLR1 SUMOylation level in PC-3 cells. We show that both TBL1 and TBLR1 are SUMOylated in response to TNF-α treatment, and this increases formation of the TBL1-TBLR1-NF-κB complex, which leads to NF-κB-mediated transcriptional activation of cytokine gene expression. Conversely, SENP1-mediated deSUMOylation of TBL1 and TBLR1 inhibits NF-κB-target gene expression by dissociating TBL1 and TBLR1 from the nuclear hormone receptor corepressor (NCoR) complex. TBL1 knockdown substantially suppresses inflammatory signaling and PC-3 cell proliferation. Collectively, these results suggest that targeted SUMOylation of TBL1 and TBLR1 may be a useful strategy for therapeutic treatment of androgen-independent prostate cancer.
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea.
authors.forename: Soo-Yeon
authors.initials: SY
authors.lastname: Park
authors.affiliation: College of Pharmacy, CHA University, Gyeonggi-do, Pocheon, South Korea.
authors.forename: Younghwa
authors.initials: Y
authors.lastname: Na
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea.
authors.forename: Mee-Hee
authors.initials: MH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea.
authors.forename: Jae-Sung
authors.initials: JS
authors.lastname: Seo
authors.affiliation: Department of Food Science and Nutrition, The University of Suwon, Kyunggi-do, South Korea.
authors.forename: Yoo-Hyun
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, University of Ulsan College of Medicine, Poongnap-dong, Songpa-gu, Seoul, South Korea.
authors.forename: Kyung-Chul
authors.initials: KC
authors.lastname: Choi
authors.affiliation: Division of Nutrition and Metabolism Research Group, Korea Food Research Institute, Gyeonggi-do, South Korea.
authors.forename: Hyo-Kyoung
authors.initials: HK
authors.lastname: Choi
authors.affiliation: Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea.
authors.forename: Ho-Geun
authors.initials: HG
authors.lastname: Yoon
mesh_terms: D000728:Androgens / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D058207:Sumoylation; D015293:Transducin / Q000378:metabolism*
chemical_list: D000728:Androgens; D016207:Cytokines; D018836:Inflammation Mediators; D009687:Nuclear Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C119542:TBL1X protein, human; C473691:TBL1XR1 protein, human; D015293:Transducin
keywords: NF-κB; SUMOylation; TBL1; TBLR1; inflammation