Epigenetic alteration of PRKCDBP in colorectal cancers and its implication in tumor cell resistance to TNFα-induced apoptosis
| Autor: | Hyo Jong Kim, Nam Goo Her, Sung Gil Chi, Sun Jin Park, Seong In Jeong, Min Ju Kang, Hye Yeon Han, Taekyu Ha, Byung Kyu Ryu, Kil Yeon Lee, Jin Hee Lee, Min Goo Lee, Jikhyon Han |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Colorectal cancer Blotting Western Transplantation Heterologous Mice Nude Apoptosis Biology Epigenesis Genetic Mice Cell Line Tumor Transcriptional regulation medicine Animals Humans Epigenetics Promoter Regions Genetic Cell Proliferation Reverse Transcriptase Polymerase Chain Reaction Tumor Necrosis Factor-alpha Intracellular Signaling Peptides and Proteins NF-kappa B Cancer Transfection Cell Cycle Checkpoints Neoplasms Experimental DNA Methylation medicine.disease HCT116 Cells Molecular biology Gene Expression Regulation Neoplastic Oncology Drug Resistance Neoplasm Tumor necrosis factor alpha Female RNA Interference Caco-2 Cells Colorectal Neoplasms Chromatin immunoprecipitation HT29 Cells |
| Zdroj: | Clinical cancer research : an official journal of the American Association for Cancer Research. 17(24) |
| ISSN: | 1557-3265 |
| Popis: | 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-κB 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 G1 cell-cycle arrest and increased cellular sensitivity to various apoptotic stresses. PRKCDBP was induced by TNFα, and its level correlated with tumor cell sensitivity to TNFα-induced apoptosis. PRKCDBP induction by TNFα was disrupted by blocking NF-κB signaling while it was enhanced by RelA transfection. The PRKCDBP promoter activity was increased in response to TNFα, and this response was abolished by disruption of a κB site in the promoter. PRKCDBP delayed the formation and growth of xenograft tumors and improved tumor response to TNFα-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-κB in response to TNFα. This suggests that PRKCDBP inactivation may contribute to tumor progression by reducing cellular sensitivity to TNFα and other stresses, particularly under chronic inflammatory microenvironment. Clin Cancer Res; 17(24); 7551–62. ©2011 AACR. |
| Databáze: | OpenAIRE |
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