SUMOylation of TBL1 and TBLR1 promotes androgen-independent prostate cancer cell growth

// Soo-Yeon Park 1, * , Younghwa Na 2, * , Mee-Hee Lee 1, * , Jae-Sung Seo 1 , Yoo-Hyun Lee 3 , Kyung-Chul Choi 4 , Hyo-Kyoung Choi 5 , Ho-Geun Yoon 1 1 Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea 2 College of Pharmacy, CHA University, Gyeonggi-do, Pocheon, South Korea 3 Department of Food Science and Nutrition, The University of Suwon, Kyunggi-do, South Korea 4 Department of Biomedical Sciences, University of Ulsan College of Medicine, Poongnap-dong, Songpa-gu, Seoul, South Korea 5 Division of Nutrition and Metabolism Research Group, Korea Food Research Institute, Gyeonggi-do, South Korea * These authors contributed equally to this work Correspondence to: Kyung-Chul Choi, email: choikc75@amc.seoul.kr Hyo-Kyoung Choi, email: chkyoung@kfri.re.kr Ho-Geun Yoon, email: yhgeun@yuhs.ac Keywords: SUMOylation, TBL1, TBLR1, NF-κB, inflammation Received: October 29, 2015 Accepted: March 29, 2016 Published: April 26, 2016 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.