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45. Involvement of promoter methylation in the regulation of Pregnane X receptor in colon cancer cells

Author

Otsuka Koki, Wakabayashi Go, Sugai Tamotsu, Terashima Jun, Gamo Toshie, Habano Wataru, and Ozawa Shogo

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Background Pregnane X receptor (PXR) is a key transcription factor that regulates drug metabolizing enzymes such as cytochrome P450 (CYP) 3A4, and plays important roles in intestinal first-pass metabolism. Although there is a large inter-individual heterogeneity with intestinal CYP3A4 expression and activity, the mechanism driving these differences is not sufficiently explained by genetic variability of PXR or CYP3A4. We examined whether epigenetic mechanisms are involved in the regulation of PXR/CYP3A4 pathways in colon cancer cells. Methods mRNA levels of PXR, CYP3A4 and vitamin D receptor (VDR) were evaluated by quantitative real-time PCR on 6 colon cancer cell lines (Caco-2, HT29, HCT116, SW48, LS180, and LoVo). DNA methylation status was also examined by bisulfite sequencing of the 6 cell lines and 18 colorectal cancer tissue samples. DNA methylation was reversed by the treatment of these cell lines with 5-aza-2'-deoxycytidine (5-aza-dC). Results The 6 colon cancer cell lines were classified into two groups (high or low expression cells) based on the basal level of PXR/CYP3A4 mRNA. DNA methylation of the CpG-rich sequence of the PXR promoter was more densely detected in the low expression cells (Caco-2, HT29, HCT116, and SW48) than in the high expression cells (LS180 and LoVo). This methylation was reversed by treatment with 5-aza-dC, in association with re-expression of PXR and CYP3A4 mRNA, but not VDR mRNA. Therefore, PXR transcription was silenced by promoter methylation in the low expression cells, which most likely led to downregulation of CYP3A4 transactivation. Moreover, a lower level of PXR promoter methylation was observed in colorectal cancer tissues compared with adjacent normal mucosa, suggesting upregulation of the PXR/CYP3A4 mRNAs during carcinogenesis. Conclusions PXR promoter methylation is involved in the regulation of intestinal PXR and CYP3A4 mRNA expression and might be associated with the inter-individual variability of the drug responses of colon cancer cells.

Published
2011
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47. Additional file 2: Table S2. of Analysis of the DNA methylation level of cancer-related genes in colorectal cancer and the surrounding normal mucosa

Author

Sugai, Tamotsu, Yoshida, Masakazu, Eizuka, Makoto, Uesugii, Noriyuki, Habano, Wataru, Otsuka, Kouki, Sasaki, Akira, Yamamoto, Eiichiro, Matsumoto, Takayuki, and Hiromu Suzuki

Subjects
congenital, hereditary, and neonatal diseases and abnormalities, stomatognathic diseases, hemic and lymphatic diseases, neoplasms, digestive system diseases
Abstract

Relationship of DNA methylation status to expression of CDKN2A and MLH1 in colorectal carcinoma.

Published
2017
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