Epigenetic Alteration of PRKCDBP in Colorectal Cancers and Its Implication in Tumor Cell Resistance to TNFα-Induced Apoptosis

Abstract

Purpose: PRKCDBP is a putative tumor suppressor in which alteration has been observed in several human cancers. We investigated expression and function of PRKCDBP in colorectal cells and tissues to explore its candidacy as a suppressor in colorectal tumorigenesis.Experimental Design: Expression and methylation status of PRKCDBP and its effect on tumor growth were evaluated. Transcriptional regulation by NF-kB signaling was defined by luciferase reporter and chromatin immunoprecipitation assays.Results: PRKCDBP expression was hardly detectable in 29 of 80 (36%) primary tumors and 11 of 19 (58%) cell lines, and its alteration correlated with tumor stage and grade. Promoter hypermethylation was commonly found in cancers. PRKCDBP expression induced the G 1 cell-cycle arrest and increased cellular sensitivity to various apoptotic stresses. PRKCDBP was induced by TNFa, and its level correlated with tumor cell sensitivity to TNFa-induced apoptosis. PRKCDBP induction by TNFa was disrupted by blocking NF-kB signaling while it was enhanced by RelA transfection. The PRKCDBP promoter activity was increased in response to TNFa, and this response was abolished by disruption of a kB site in the promoter. PRKCDBP delayed the formation and growth of xenograft tumors and improved tumor response to TNFa-induced apoptosis.Conclusions: PRKCDBP is a proapoptotic tumor suppressor which is commonly altered in colorectal cancer by promoter hypermethylation, and its gene transcription is directly activated by NF-kB in response to TNFa. This suggests that PRKCDBP inactivation may contribute to tumor progression by reducing cellular sensitivity to TNFa and other stresses, particularly under chronic inflammatory microenvironment. Clin Cancer Res; 17(24); 7551-62. Ó2011 AACR.

Elevation of PRKCDBP, A Novel Transcriptional Target of TNF-α, and Its Downregulation by Infliximab in Patients with Ulcerative Colitis

“…Discussion TNF-a is a critical proinflammatory cytokine, and its downregulation in the colonic mucosa is associated with regressed inflammation in patients with moderate-to-severe UC [13,15]. A recent study showed that PRKCDBP, a proapoptotic tumor suppressor gene, is a direct transcriptional target of TNF-a/NF-jB signaling, and its expression is frequently lost or downregulated in human colorectal cancer [22]. Despite this, the expression status of PRKCDBP in human IBD has not yet been defined.…”

“…PRKCDBP expression is frequently downregulated in many types of malignancy, including colorectal cancer, due to aberrant promoter CpG site hypermethylation [18][19][20][21]. Activation of PRKCDBP induces cell cycle arrest and apoptosis by enhancing p53 protein stability, while its inactivation contributes to tumor growth and increased resistance to TNF-a-induced apoptosis [22]. It was also demonstrated that PRKCDBP is a transcription target of TNF-a, which plays a crucial role in colonic inflammation and tumorigenesis [22].…”

“…Activation of PRKCDBP induces cell cycle arrest and apoptosis by enhancing p53 protein stability, while its inactivation contributes to tumor growth and increased resistance to TNF-a-induced apoptosis [22]. It was also demonstrated that PRKCDBP is a transcription target of TNF-a, which plays a crucial role in colonic inflammation and tumorigenesis [22]. Additionally, TNF-a plays a key role in the immunopathogenesis of IBD.…”

Association of Aberrant Methylation at Promoter Regions of Tumor Suppressor Genes with Placental Pathologies

“…These tumor suppressor genes are involved in regulating cellular differentiation, senescence, apoptosis, cell cycle arrest, DNA repair, microtubule dynamics and genomic instability [8][9][10][11][12][13]. Silencing of tumor suppressor genes mediated by DNA methylation is a hallmark of human cancer [14].…”

Gene Expression Profiling of Human c-Kit Mutant D816V

“…MOAP1 gene encodes protein which functionally mediates caspase-dependent apoptosis by its interaction with apoptosis regulator protein [37]. The gene encoding protein kinase C delta binding protein, PRKCDBP expression has been shown to induce the G1 cell-cycle arrest and increased cellular sensitivity to various apoptotic stresses [38]. The expression of this protein was found to be down-regulated in various cancer cell lines, suggesting the possible tumor suppressor function of this protein.…”