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METTL3-mediated RNA m6A Hypermethylation Promotes Tumorigenesis and GH Secretion of Pituitary Somatotroph Adenomas
- Source :
- The Journal of Clinical Endocrinology & Metabolism. 107:136-149
- Publication Year :
- 2021
- Publisher :
- The Endocrine Society, 2021.
-
Abstract
- Introduction Pituitary growth hormone-secreting (GH) pituitary adenomas (PAs) cause mass effects and dysregulated hypersecretion of GH. However, somatic mutation burden is low in PAs. While progress has been made in identifying the epigenetic changes involved in GH-PA initiation, the precise details of its tumorigenesis in GH-PA patients remains to be elucidated. As N6-methyladenosine (m6A) has been shown to often play a critical role in various tumors, it represents a possible initiation point for the tumorigenesis of pituitary adenomas. However, the role of RNA methylation in GH adenomas remains unclear. Methods Protein expression of m6A regulators was measured by immunohistochemistry. Global levels and distribution of m6A methylation were separately analyzed by m6A enzyme-linked immunosorbent assay and m6A sequencing (m6A-seq). RNA interference and lentivirus knockdown system were used to investigate the role of methyltransferase-like 3 (METTL3) and its m6A- dependent regulatory mechanism in tumor progression and GH secretion. Results We show that both METTL3 messenger RNA and protein expression are elevated in GH-PA samples when compared with both normal pituitary tissue specimens and nonsecreting pituitary adenomas. Levels of m6A modification increased in GH-PAs, and hypermethylated RNAs are involved in hormone secretion and cell development. Knockdown of METTL3 in GH3 cell line resulted in decreased cell growth and GH secretion. Importantly, we found that GNAS and GADD45γ act as the downstream targets in this process. Conclusion Our findings strongly suggest that m6A methyltransferase METTL3 promotes tumor growth and hormone secretion by increasing expression of GNAS and GADD45γ in a m6A-dependent manner. Thus, METTL3 and the methylated RNAs constitute suitable targets for clinical treatment of GH-PAs.
- Subjects :
- Adenoma
Adult
Male
medicine.medical_specialty
Adenosine
Carcinogenesis
Endocrinology, Diabetes and Metabolism
Clinical Biochemistry
Biology
medicine.disease_cause
Methylation
Biochemistry
Epigenesis, Genetic
Young Adult
Endocrinology
Pituitary adenoma
RNA interference
Cell Line, Tumor
Internal medicine
Acromegaly
Chromogranins
GTP-Binding Protein alpha Subunits, Gs
medicine
GNAS complex locus
Humans
Pituitary Neoplasms
Aged
Cell Proliferation
Aged, 80 and over
Gene knockdown
Human Growth Hormone
Biochemistry (medical)
Intracellular Signaling Peptides and Proteins
Methyltransferases
Middle Aged
medicine.disease
Growth hormone secretion
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Pituitary Gland
DNA methylation
biology.protein
RNA
Female
Growth Hormone-Secreting Pituitary Adenoma
Subjects
Details
- ISSN :
- 19457197 and 0021972X
- Volume :
- 107
- Database :
- OpenAIRE
- Journal :
- The Journal of Clinical Endocrinology & Metabolism
- Accession number :
- edsair.doi.dedup.....9d7982985542d763a56aad58b33c3cc0