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

Chronic inflammation is strongly associated with prostate cancer pathogenesis. Transducin beta-like protein (TBL1) and Transducin beta-like 1X-linked receptor 1 (TBLR1) have been identified recently as a coactivator for NF-kappa B-mediated transcription; however, the underlying mechanism by which TBL1 and TBLR1 activate NF-kappa B 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-alpha treatment, and this increases formation of the TBL1-TBLR1-NF-kappa B complex, which leads to NF-kappa B-mediated transcriptional activation of cytokine gene expression. Conversely, SENP1-mediated deSUMOylation of TBL1 and TBLR1 inhibits NF-kappa B-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.