Changes in DNA 5-Hydroxymethylcytosine Levels and the Underlying Mechanism in Non-functioning Pituitary Adenomas.

Yiwen Xu,Hui You,Huijuan Zhu,Yong Yao,Fengying Gong,Lin Lu,Shi Chen,Yamei Niu,Hui Pan,Kan Deng,Renzhi Wang,Wei-Min Tong,Feng Feng

doi:10.3389/fendo.2020.00361

Abstract

Epigenetic factors have been proven to contribute to pituitary adenoma formation. 5-hydroxymethylcytosine (5hmC), which is catalyzed by ten-eleven translocation 2 (TET2), is related to DNA demethylation. In order to explore the pathogenesis of non-functioning pituitary adenomas (NFPAs), we detected genomic 5hmC levels in 57 NFPAs and 5 normal pituitary glands, and TET2 expression, distribution and TET2 alteration. Genomic 5hmC levels in NFPAs were significantly lower than those in normal pituitary glands (0.38‰ (0.24‰, 0.61‰) vs. 2.47‰ (1.56‰, 2.83‰), P < 0.0001). There was positive correlation of 5hmC levels with TET2 total and nuclear expression in NFPAs (r = 0.461, P = 0.018; r = 0.458, P = 0.019). Genomic 5hmC levels in NFPAs with TET2 p.P29R were significantly lower than those in wild type NFPAs (0.33 ± 0.18‰ vs. 0.51 ± 0.25‰, P = 0.021). We found genomic 5hmC loss in human NFPAs for the first time. Genomic 5hmC levels may be affected by TET2 expression, subcellular localization and TET2 mutation.

Highlights

Pituitary adenomas (PAs) derive from adenohypophysis and account for 15–25% of all intracranial tumors [1, 2]
Genomic 5hmC Levels Were High in Normal Pituitary Glands and Lost in non-functioning pituitary adenomas (NFPAs)
Compared with those in normal pituitary glands, genomic 5hmC levels were significantly decreased in NFPAs [0.38‰ (0.24‰, 0.61‰) vs. 2.47‰ (1.56‰, 2.83‰), P < 0.0001], and genomic 5caC levels were significantly increased [0.20‰ (0.18‰, 0.21‰) vs. 0.16‰ (0.15‰, 0.18‰), P = 0.005] (Figures 1B,D)

Summary

Introduction

Pituitary adenomas (PAs) derive from adenohypophysis and account for 15–25% of all intracranial tumors [1, 2]. The pathogenesis of PAs are associated with activation of oncogenes, inactivation of tumor suppressor genes, changes in epigenetic modification, dysregulation of miRNAs, dysregulation of cytokines and growth factors, hormone stimulation, etc. Despite of these findings, the exact mechanism is still unclear [1, 3]. Epigenetic changes have been revealed in tumor suppressor genes, such as CDKN1A, GADD45y, FGFR2, and caspase-8; 5hmC Levels in NFPAs oncogenes, such as MAGEA3, and PTTG; imprinted genes, such as GNAS1, NNAT, and MEG3; epigenome modifiers, such as DNMT3b; and transcription regulators, such as Ik, HMGA2 [4]

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Results

Conclusion