Abstract 1297: SETD6-mediated deregulation of NF- κB signaling in 4-ABP-induced bladder carcinogenesis.

Abstract Epidemiological data support an etiological role for chemicals from occupational exposure and cigarette smoke with increased risk of bladder cancer. However, epigenetic effects of these chemicals remain to be elucidated. Protein methyltransferases (PMTs) methylate protein lysine and arginine residues and play an important role in regulating gene transcription. Deregulation of SET-domain-containing PMTs has a crucial role in carcinogenesis. SETD6 has been shown to monomethylate RelA (a principal subunit of NF-κB at Lys310). Monomethylated RelA recruits GLP (G9A-like protein), a histone dimethyl transferase to the NF-κB target genes, which results in transcriptional repression. The role of SETD6 in bladder cancer is unknown. We used qPCR and immunoblotting to determine changes in SETD6 at the mRNA and protein level in bladder cancer cells relative to primary urothelial cells. We also found that knockdown of SETD6 significantly decreases the viability and proliferation of bladder cancer cells suggesting that SETD6 may function as an oncogene in bladder cancer. Furthermore, we also found that message and protein levels of SETD6 are induced in primary urothelial cells following treatment of 4-aminobiphenyl (4-ABP), an important constituent of cigarette smoke. Preliminary results indicate that induction may be mediated by 4-ABP-induced ROS. RelAK310Me1 level also increased with 4-ABP treatment showing the increase in SETD6 functional activity with 4-ABP exposure. We also found the decrease in expression of RelB, one of the target genes of RelA. Overall our results show that SETD6 may function as an oncogene in 4-ABP induced bladder cancer by deregulating transactivation property of RelA. These results show for the first time the relevance of PKMTs and epigenetic regulation of NF-κB in carcinogen induced bladder cancer. Supported by RO3 CA136058 (RG). Citation Format: Neelam Mukherjee, Rita Ghosh. SETD6-mediated deregulation of NF- κB signaling in 4-ABP-induced bladder carcinogenesis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1297. doi:10.1158/1538-7445.AM2013-1297