Epigenetic alteration of PRKCDBP in colorectal cancers and its implication in tumor cell resistance to TNFα-induced apoptosis

Jin Hee Lee, Min Ju Kang, Hye Yeon Han, Min Goo Lee, Seong In Jeong, Byung Kyu Ryu, Tae Kyu Ha, Nam Goo Her, Jikhyon Han, Sun Jin Park, Kil Yeon Lee, Hyo Jong Kim, Sung-Gil Chi

Research output: Contribution to journalArticle

27 Citations (Scopus)

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-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 G 1 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.

Original languageEnglish
Pages (from-to)7551-7562
Number of pages12
JournalClinical Cancer Research
Volume17
Issue number24
DOIs
Publication statusPublished - 2011 Dec 15

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Epigenomics
Colorectal Neoplasms
Apoptosis
Neoplasms
Gastrin-Secreting Cells
Chromatin Immunoprecipitation
Growth
Cell Cycle Checkpoints
Luciferases
Heterografts
Methylation
Transfection
Carcinogenesis
Research Design
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Epigenetic alteration of PRKCDBP in colorectal cancers and its implication in tumor cell resistance to TNFα-induced apoptosis. / Lee, Jin Hee; Kang, Min Ju; Han, Hye Yeon; Lee, Min Goo; Jeong, Seong In; Ryu, Byung Kyu; Ha, Tae Kyu; Her, Nam Goo; Han, Jikhyon; Park, Sun Jin; Lee, Kil Yeon; Kim, Hyo Jong; Chi, Sung-Gil.

In: Clinical Cancer Research, Vol. 17, No. 24, 15.12.2011, p. 7551-7562.

Research output: Contribution to journalArticle

Lee, JH, Kang, MJ, Han, HY, Lee, MG, Jeong, SI, Ryu, BK, Ha, TK, Her, NG, Han, J, Park, SJ, Lee, KY, Kim, HJ & Chi, S-G 2011, 'Epigenetic alteration of PRKCDBP in colorectal cancers and its implication in tumor cell resistance to TNFα-induced apoptosis', Clinical Cancer Research, vol. 17, no. 24, pp. 7551-7562. https://doi.org/10.1158/1078-0432.CCR-11-1026
Lee, Jin Hee ; Kang, Min Ju ; Han, Hye Yeon ; Lee, Min Goo ; Jeong, Seong In ; Ryu, Byung Kyu ; Ha, Tae Kyu ; Her, Nam Goo ; Han, Jikhyon ; Park, Sun Jin ; Lee, Kil Yeon ; Kim, Hyo Jong ; Chi, Sung-Gil. / Epigenetic alteration of PRKCDBP in colorectal cancers and its implication in tumor cell resistance to TNFα-induced apoptosis. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 24. pp. 7551-7562.
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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-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 G 1 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.",
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AU - Lee, Jin Hee

AU - Kang, Min Ju

AU - Han, Hye Yeon

AU - Lee, Min Goo

AU - Jeong, Seong In

AU - Ryu, Byung Kyu

AU - Ha, Tae Kyu

AU - Her, Nam Goo

AU - Han, Jikhyon

AU - Park, Sun Jin

AU - Lee, Kil Yeon

AU - Kim, Hyo Jong

AU - Chi, Sung-Gil

PY - 2011/12/15

Y1 - 2011/12/15

N2 - 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 G 1 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.

AB - 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 G 1 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.

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