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.
Highlights
Chronic inflammation leads to a wide variety of diseases, such as rheumatoid arthritis, other autoimmune disorders, cardiovascular disease, gastrointestinal disorders, and several cancers [1, 2]
A recent study reported that the transducing β-like 1X-linked protein (TBL1) corepressor acts as a cofactor for recruiting p65 to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) target gene promoters, which eventually leads to the transcriptional activation of inflammatory cytokines [23]
A recent study reported that TBL1 was required for p65 recruitment to NF-κB-targeted gene promoters in response to TNF-α [23], which suggests an additional role for TBL1 as a transcriptional activator
Summary
Chronic inflammation leads to a wide variety of diseases, such as rheumatoid arthritis, other autoimmune disorders, cardiovascular disease, gastrointestinal disorders, and several cancers [1, 2]. Chronic inflammation is one of the most important factors in prostate cancer etiology and carcinogenesis, and plasma IL-6 level has prognostic significance in patients with hormone-refractory prostate cancer [5, 6]. A fiveyear follow-up study for men who had abnormal serum prostate-specific antigen (PSA) levels and/or digital rectal examinations (DRE) reported that chronic inflammation is a significant risk factor in the development of prostate cancer [7]. Increased levels of NF-κB and IL-6 are implicated in the development of prostate cancer cell chemoresistance [14]. These combined studies suggest that NF-κB may be a promising target for improving chemotherapeutic efficacy in prostate cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
