Epigenetic Regulation of Vitamin D Metabolism in Human Lung Adenocarcinoma

Overview

Journal J Thorac Oncol

Publisher Elsevier

Specialties Oncology
Pulmonary Medicine

Date 2014 Apr 17

PMID 24736069

Citations 12

Authors

Nithya Ramnath

Ernest Nadal

Chae Kyung Jeon

Juan Sandoval

Justin Colacino

Laura S Rozek

Paul J Christensen

Manel Esteller

David G Beer

So Hee Kim

Affiliations

Soon will be listed here.

Abstract

Introduction: 1α,25-Dihydroxyvitamin D3 (1,25-D3) is antiproliferative in preclinical models of lung cancer, but in tumor tissues, its efficacy may be limited by CYP24A1 expression. CYP24A1 is the rate limiting catabolic enzyme for 1,25-D3 and is overexpressed in human lung adenocarcinoma (AC) by unknown mechanisms.

Methods: The DNA methylation status of CYP24A1 was determined by bisulfite DNA pyrosequencing in a panel of 30 lung cell lines and 90 surgically resected lung AC. The level of CYP24A1 methylation was correlated with CYP24A1 expression in lung AC cell lines and tumors. In addition, histone modifications were assessed by quantitative chromatin immunoprecipitation-polymerase chain reaction (ChIP-qPCR) in A549, NCI-H460, and SK-LU-1.

Results: Bisulfite DNA pyrosequencing analysis revealed that CYP24A1 gene was heterogeneously methylated in lung AC. Expression of CYP24A1 was inversely correlated with promoter DNA methylation in lung AC cell lines and tumors. Treatment with 5-aza-2'-deoxycytidine (5-Aza) and trichostatin A (TSA) increased CYP24A1 expression in lung AC. We observed that CYP24A1 promoter hypermethylation decreased CYP24A1 enzyme activity in vitro, whereas treatment with 5-Aza and/or TSA increased CYP24A1 enzyme affinity for its substrate 1,25-D3. In addition, ChIP-qPCR analysis revealed specific histone modifications within the CYP24A1 promoter region. Treatment with TSA increased H3K4me2 and H3K9ac and simultaneously decreased H3K9me2 at the CYP24A1 promoter and treatment with 5-Aza and/or TSA increased the recruitment of vitamin D receptor (VDR) to vitamin D response elements (VDRE) of the CYP24A1 promoter.

Conclusions: The expression of CYP24A1 gene in human lung AC is in part epigenetically regulated by promoter DNA methylation and repressive histone modifications. These findings should be taken into consideration when targeting CYP24A1 to optimize antiproliferative effects of 1,25-D3 in lung AC.

Citing Articles

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Association of DNA methylation of vitamin D metabolic pathway related genes with colorectal cancer risk.

Wang Y, Li L, Deng X, Fang Y, Zhang C Clin Epigenetics. 2023; 15(1):140.

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Interplay of Vitamin D and SIRT1 in Tissue-Specific Metabolism-Potential Roles in Prevention and Treatment of Non-Communicable Diseases Including Cancer.

Nemeth Z, Patonai A, Simon-Szabo L, Takacs I Int J Mol Sci. 2023; 24(7).

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Zeng R, Li H, Jia L, Lee S, Jiang R, Zhang Y BMC Cancer. 2022; 22(1):1317.

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