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Background: Growth hormone (GH)-secreting pituitary adenomas can be divided into densely and sparsely granulated subtypes, based on electron microscopic studies. The latter are frequently associated with more invasive behavior, and respond worse to somatostatin analogues. The underlining mechanisms are largely unknown. Increasing evidence showed that N6-methyladenosine (m6A) of messenger RNAs (mRNAs) participated in the development of various tumors. We aimed to investigate the role of RNA m6A modification in the classification of GH-secreting pituitary adenomas. Methods: The main components of m6A methyltransferase complex, demethylase, and RNA m6A levels were compared between sparsely and densely GH-secreting tumors. The role of METTL3 was functionally studied. Results: The level of m6A methyltransferases (METTL3, WTAP and METTL14) and demethylase (FTO and ALKBH5) were significantly downregulated in GH adenomas, comparing to the normal pituitary tissues. However, only METTL3 and METTL14 were shown to significantly higher in densely granulated tumors than those in sparsely ones. Consistently, the level of RNA m6A was markedly increased in densely granulated GH adenomas. In addition, the expression of METTL3 was positively correlated with the level of RNA m6A among tumor samples, and METTL3 silencing decreased RNA m6A of GH3 cells. METTL3 was demonstrated to function as a tumor suppressor based on in vivo and in vitro evidence, using patient-derived and GH3 cells. Moreover, the sensitivity of GH3 cells to pasireotide was increased with METTL3 overexpression, but decreased when METTL3 was silenced. Consistently, METTL3 silencing inhibited GH secretory, and decreased the expression of SSTR2 and SSTR5. Conclusions: METTL3 functions as a tumor suppressor in GH secreting adenomas, and enhance tumor cells sensitivity to medical treatment. Our work uncovers the critical roles of METTL3 in the pathogenesis of GH adenomas, since it potentially promotes the transition from sparsely to densely granulated subtypes.

SAT-LB61 METTL3 Promotes Sparsely Granulated GH-Secreting Pituitary Adenomas to Behavior as Densely Granulated Adenomas