SUMOylation of TBL1 and TBLR1 promotes androgen-independent prostate cancer cell growth
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Soo-Yeon Park1,*, Younghwa Na2,*, Mee-Hee Lee1,*, Jae-Sung Seo1, Yoo-Hyun Lee3, Kyung-Chul Choi4, Hyo-Kyoung Choi5, Ho-Geun Yoon1
1Department of Biochemistry and Molecular Biology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seodaemun-gu, Seoul, South Korea
2College of Pharmacy, CHA University, Gyeonggi-do, Pocheon, South Korea
3Department of Food Science and Nutrition, The University of Suwon, Kyunggi-do, South Korea
4Department of Biomedical Sciences, University of Ulsan College of Medicine, Poongnap-dong, Songpa-gu, Seoul, South Korea
5Division of Nutrition and Metabolism Research Group, Korea Food Research Institute, Gyeonggi-do, South Korea
*These authors contributed equally to this work
Kyung-Chul Choi, email: firstname.lastname@example.org
Hyo-Kyoung Choi, email: email@example.com
Ho-Geun Yoon, email: firstname.lastname@example.org
Keywords: SUMOylation, TBL1, TBLR1, NF-κB, inflammation
Received: October 29, 2015 Accepted: March 29, 2016 Published: April 26, 2016
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.
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