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.
Oncotarget. 2016 Apr 26 [Epub ahead of print]
Park Soo-Yeon, Na Younghwa, Lee Mee-Hee, Seo Jae-Sung, Lee Yoo-Hyun, Choi Kyung-Chul, Choi Hyo-Kyoung, Yoon Ho-Geun
Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea., College of Pharmacy, CHA University, Gyeonggi-do, Pocheon, South Korea., Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea., Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea., Department of Food Science and Nutrition, The University of Suwon, Kyunggi-do, South Korea., Department of Biomedical Sciences, University of Ulsan College of Medicine, Poongnap-dong, Songpa-gu, Seoul, South Korea., Division of Nutrition and Metabolism Research Group, Korea Food Research Institute, Gyeonggi-do, South Korea., Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea.