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Hypoxic‐stabilized EPAS1 proteins transactivate DNMT1 and cause promoter hypermethylation and transcription inhibition of EPAS1 in non‐small cell lung cancer
Author(s) -
Xu XiangHong,
Bao Yang,
Wang Xiaotian,
Yan Fengyang,
Guo Shicheng,
Ma Yanyun,
Xu Dong,
Jin Li,
Xu Jibin,
Wang Jiucun
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201700715
Subject(s) - biology , dna methylation , cancer research , lung cancer , methyltransferase , transcription factor , carcinogenesis , methylation , microbiology and biotechnology , tumor suppressor gene , hif1a , gene expression , cancer , gene , pathology , medicine , genetics , angiogenesis
Non‐small cell lung cancer (NSCLC) is the leading cause of cancer mortality globally. Although cigarette smoking is by far the most important risk factor for lung cancer, the aberrant expression of oncogenes and tumor suppressor genes contributes a great deal to tumorigenesis. Here, we reveal that aberrant expression of endothelial PAS domain‐containing protein 1 (EPAS1) gene, which encodes hypoxia inducible factor 2a, has a critical role in NSCLC. Our results showed EPAS1 mRNA was down‐regulated in 82.5% of NSCLC tissues, and a new region of EPAS1 promoter was found to be highly methylated in lung cancer cell lines and NSCLC tissues. Moreover, the methylation rates were negatively correlated to EPAS1 mRNA expression in lung tissues. Further, demethylation analysis demonstrated EPAS1 was regulated by DNA methyltransferases (DNMTs) in NSCLC. In contrast, DNMT1 was verified as an EPAS1 target gene by chromatin immunoprecipitation assay and could be transactivated by stabilized EPAS1 proteins in hypoxic lung cells, thereby decreasing EPAS1 mRNA expression by methylation regulation. Collectively, our study suggests there might be a mechanism of negative‐feedback regulation for EPAS1 in NSCLC. That is, hypoxic‐stabilized EPAS1 proteins transactivated ΌΝΜΤΊ , which further promoted the hypermethylation of EPAS1 promoter and decreased EPAS1 mRNA expression levels in NSCLC.—Xu, X.‐H., Bao, Y., Wang, X., Yan, F., Guo, S., Ma, Y., Xu, D., Jin, L., Xu, J., Wang, J. Hypoxic‐stabilized EPAS1 proteins transactivate DNMT1 and cause promoter hypermethylation and transcription inhibition of EPAS1 in non‐small cell lung cancer. FASEB J. 32, 6694–6705 (2018). www.fasebj.org