Purpose: PRKCDBP is a putative tumor suppressor whose 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 NFkB signaling was defined using 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 G1 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 NFkB 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 NFkB 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.
- Received April 24, 2011.
- Revision received September 24, 2011.
- Accepted October 3, 2011.
- Copyright © 2011, American Association for Cancer Research.