Thymic epithelial tumors (TETs) are rare neoplasms, originated from epithelial thymic cells. The oncogenic potential of these rare neoplasms is still largely undefined and a deeper molecular characterization could result in a relevant advance in their management greatly improving diagnosis, prognosis and treatment choice. Deregulation of N6-methyladenosine (m6A) RNA modification, catalyzed by the METTL3/METTL14 methyltransferase complex, is emerging as a relevant event in stem differentiation and carcinogenesis. Various studies have reported that altered expression of METTL3 is associated with an aggressive malignant phenotype, and favors migration and invasiveness. In this study, we characterized the METTL3 contribution to TET phenotype. We evidenced that METTL3 is over-expressed in tumoral tissue compared to normal counterpart. Of note, we observed that the silencing of METTL3 in a thymic carcinoma cell line (TC1889) results in a reduction of cell growth and proliferation. Of note, METTL3 is responsible for the methylation and induction of c-MYC expression in TET cells. Specifically, high expression of c-MYC protein is enabled by lncRNA MALAT1, which is methylated and delocalized by METTL3. Finally, we evidenced that the reduction of METTL3 expression improves the cell death induced by chemoterapic agents or c-Myc inhibitors treatment. Our results support an oncogenic role for METTL3 in TETs, highlighting this molecule as a novel potential therapeutic target for TET management.

METTL3 contribution to cell proliferation in Thymic Epithelial Tumor Cells / Iaiza, Alessia; Tito, Claudia; Ianniello, Zaira; Ganci, Federica; Laquintana, Valentina; Gallo, Enzo; Sacconi, Andrea; Masciarelli, Silvia; De Angelis, Luciana; Aversa, Sara; Diso, Daniele; Anile, Marco; Petrozza, Vincenzo; Facciolo, Francesco; Melis, Enrico; Pescarmona, Edoardo; Venuta, Federico; Marino, Mirella; Blandino, Giovanni; Fontemaggi, Giulia; Fatica, Alessandro; Fazi, Francesco. - (2022). ((Intervento presentato al convegno EMBO Workshop: The epitranscriptome tenutosi a Heidelberg; Germany.

METTL3 contribution to cell proliferation in Thymic Epithelial Tumor Cells

Alessia Iaiza;Claudia Tito;Zaira Ianniello;Silvia Masciarelli;Luciana De Angelis;Sara Aversa;Daniele Diso;Marco Anile;Vincenzo Petrozza;Federico Venuta;Alessandro Fatica
;
Francesco Fazi
2022

Abstract

Thymic epithelial tumors (TETs) are rare neoplasms, originated from epithelial thymic cells. The oncogenic potential of these rare neoplasms is still largely undefined and a deeper molecular characterization could result in a relevant advance in their management greatly improving diagnosis, prognosis and treatment choice. Deregulation of N6-methyladenosine (m6A) RNA modification, catalyzed by the METTL3/METTL14 methyltransferase complex, is emerging as a relevant event in stem differentiation and carcinogenesis. Various studies have reported that altered expression of METTL3 is associated with an aggressive malignant phenotype, and favors migration and invasiveness. In this study, we characterized the METTL3 contribution to TET phenotype. We evidenced that METTL3 is over-expressed in tumoral tissue compared to normal counterpart. Of note, we observed that the silencing of METTL3 in a thymic carcinoma cell line (TC1889) results in a reduction of cell growth and proliferation. Of note, METTL3 is responsible for the methylation and induction of c-MYC expression in TET cells. Specifically, high expression of c-MYC protein is enabled by lncRNA MALAT1, which is methylated and delocalized by METTL3. Finally, we evidenced that the reduction of METTL3 expression improves the cell death induced by chemoterapic agents or c-Myc inhibitors treatment. Our results support an oncogenic role for METTL3 in TETs, highlighting this molecule as a novel potential therapeutic target for TET management.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11573/1610957
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