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13 July 2018 : Laboratory Research

Overexpression of DNA (Cytosine-5)-Methyltransferase 1 (DNMT1) And DNA (Cytosine-5)-Methyltransferase 3A (DNMT3A) Is Associated with Aggressive Behavior and Hypermethylation of Tumor Suppressor Genes in Human Pituitary Adenomas

Hou-Shi Ma12ABC, Elaine Lu Wang34ABC, Wen-Fei Xu5AC, Shozo Yamada6AC, Katsuhiko Yoshimoto7DEG, Zhi Rong Qian8ACE, Long Shi2AC, Li-Li Liu1ACDE, Xu-Hui Li2ABCDE*

DOI: 10.12659/MSM.910608

Med Sci Monit 2018; 24: LBR4841-4850

Abstract

BACKGROUND: Alteration of DNA methylation of tumor suppressor genes (TSGs) is one of the most consistent epigenetic changes in human cancers. DNMTs play several important roles in DNA methylation and development of cancers. Regarding DNMTs protein expressions, little is known about the clinical significance and correlation with promoter methylation status of TSGs in human pituitary adenomas.

MATERIAL AND METHODS: We analyzed the protein expression of 3 DNMTs using immunohistochemistry and assessed DNA hypermethylation of RASSF1A, CDH13, CDH1, and CDKN2A (p16) in 63 pituitary adenomas. We examined associations between DNMTs expression and clinicopathological features or promoter methylation status of TSGs.

RESULTS: Overexpression of DNMTs was detected in pituitary adenomas. Frequencies of DNMT1 overexpression were significantly higher in macroadenomas, invasive tumors, and grade III and IV tumors. DNMT3A was frequently detected in invasive tumors and grade IV tumors. In addition, DNMT1 and DNMT3A were frequently detected in high-methylation tumors. Furthermore, in multivariate logistic regression, the significant association between DNMT1 or DNMT3A and high-methylation status persisted after adjusting for clinicopathological features.

CONCLUSIONS: Our findings suggested that tumor overexpression of DNMT1 and DNMT3A is associated with tumor aggressive behavior and high-methylation status in pituitary adenomas. Our data support a possible role of DNMT1 and DNMT3A in TSG promoter methylation leading to pituitary adenoma invasion and suggest that inhibition of DNMTs has the potential to become a new therapeutic approach for invasive pituitary adenoma.

Keywords: Methylation, Methyltransferases, Pituitary Neoplasms

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750