title: SETD6 regulates NF-κB signaling in urothelial cell survival: Implications for bladder cancer.
abstract: Non-muscle invasive bladder cancer has a high recurrence rate of 45-70%, progressing to muscle invasive disease in about 15% of those patients over a 5-year period. Administration of the mycobacterium, Bacillus Calmette-Guerin (BCG) that induces local inflammation resulting in tumor remission in responsive patients is frequently used for treatment. BCG-treated patients with NF-κB del/del genotype have an increased risk of recurrence suggesting an important role of NF-κB in bladder cancer. Since protein methyltransferases play critical roles in modulating chromatin structure and gene expression, we screened a focused array of epigenetic modification genes to identify differential expression between normal urothelial and bladder cancer cells. We found and validated high expression of the SET-domain-containing protein methyltransferase, SETD6. SETD6 monomethylates NF-κB-p65 at lysine 310. Our results show that primary urothelial cells and normal bladder tissue have nearly undetectable message and protein level of SETD6 that increases in transformed urothelial cells and is further increased in bladder cancer cells and tissues. Overexpression of SETD6 in transformed urothelial cells increased cell survival and colony formation while knockdown in cancer cells decreased both parameters. Luciferase reporter assays showed that SETD6 induced the canonical NF-κB signaling pathway. Further, the use of catalytic SETD6 and IκBα mutant shows that SETD6 positively regulates survival by affecting p65 message, protein level and its function as determined by increased expression of NF-κB target genes. Our findings suggest that SETD6 plays an important role in NF-κB regulation and may have an important role in NF-κB-mediated local inflammatory response following BCG treatment.
authors.affiliation: Department of Urology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Neelam
authors.initials: N
authors.lastname: Mukherjee
authors.affiliation: Department of Urology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Cardenas
authors.affiliation: Department of Urology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Roble
authors.initials: R
authors.lastname: Bedolla
authors.affiliation: Department of Urology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.|Department of Pharmacology, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.|Department of Molecular Medicine and School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.|Department of Cancer Therapy and Research Center, School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Ghosh
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D011496:Protein Methyltransferases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D001749:Urinary Bladder Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D014408:Biomarkers, Tumor; D016328:NF-kappa B; D011496:Protein Methyltransferases; C562071:SETD6 protein, human
keywords: NF-κB; SETD6; bladder cancer; methyltransferase; signaling