METTL3-dependent MALAT1 delocalization drives c-Myc induction in thymic epithelial tumors

Alessia Iaiza, Claudia Tito, Zaira Ianniello, Federica Ganci, Valentina Laquintana, Enzo Gallo, Andrea Sacconi, Silvia Masciarelli, Luciana De Angelis, Sara Aversa, Daniele Diso, Marco Anile, Vincenzo Petrozza, Francesco Facciolo, Enrico Melis, Edoardo Pescarmona, Federico Venuta, Mirella Marino, Giovanni Blandino, Giulia FontemaggiAlessandro Fatica, Francesco Fazi

Research output: Contribution to journalArticle


Background: Thymic epithelial tumors (TETs) are rare neoplasms, originating 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 cell differentiation and carcinogenesis. Various studies have reported that altered expression of METTL3 is associated with an aggressive malignant phenotype and favors migration and invasiveness, but its role in Thymic Tumors remains unknown. Results: In this study, we characterized that METTL3 contributes to Thymic Epithelial Tumor phenotype. We evidenced that METTL3 is overexpressed in tumor tissue compared to normal counterpart. Silencing of METTL3 expression in thymic carcinoma cells results in reduced cell proliferation and overall translation rate. Of note, METTL3 is responsible for the 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. Interestingly, blocking of c-MYC by using JQ1 inhibitor cooperates with METTL3 depletion in the inhibition of proliferation and induction of cell death. Conclusion: This study highlighted METTL3 as a tumor promoter in Thymic tumors and c-MYC as a promising target to be exploited for the treatment of TET.
Original languageEnglish
Pages (from-to)173-187
Number of pages15
JournalClinical Epigenetics
Publication statusPublished - 2021


  • 6
  • A
  • Cells, Cultured
  • DNA Methylation
  • Gene Expression Regulation, Neoplastic
  • Humans
  • JQ1 inhibitor
  • MALAT1
  • METTL3
  • Methyltransferases
  • Neoplasms, Glandular and Epithelial
  • Proto-Oncogene Proteins c-myc
  • S6K1
  • Thymic carcinoma
  • Thymic epithelial tumors
  • Thymus Neoplasms
  • Transcription Factors
  • c-MYC
  • lncRNAs
  • m


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