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

Abstract

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.

The bromodomain inhibitor JQ1 up-regulates the long non-coding RNA MALAT1 in cultured human hepatic carcinoma cells

“…In addition, the MALAT1 expression level is negatively correlated with the survival rate in cancer patients 28 . MALAT1 induces cell proliferation and metastasis via the MAPK/ERK and PI3K/AKT signaling pathways in retinoblastoma and ovarian cancer, respectively 29 , 30 , and it is known to enable the high expression of the key oncogene MYC in thymic epithelial tumors 31 . Interestingly, in HepG2 cells, MALAT1 was also found in mitochondria, and its knockdown limited ATP synthesis and tumor cell invasion 32 .…”

Thymic Epithelial Neoplasms: Focusing on the Epigenetic Alterations

“…Furthermore, Iaiza et al found that the methyltransferase METTL3 is overexpressed in TEN and responsible for the induction of c-MYC expression through methylation and delocalization of the lncRNA MALAT1. Silencing of METTL3 combined with cisplatin or c-MYC inhibitor promotes apoptosis in TEN cells [ 49 ]. Bisulfite pyrosequencing in 46 TEN and 20 paired thymus tissues revealed higher promoter methylation of G protein subunit gamma 4 (GNG4), growth hormone secretagogue receptor (GHSR), homeobox D9 (HOXD9) and spalt like transcription factor 3 (SALL3) in TC than in thymoma.…”

Current Advances in N6-Methyladenosine Methylation Modification During Bladder Cancer

“…METTL3 in human tissue is highly expressed and conserved, especially in the testes. Recent studies reported that METTL3 is significantly highly expressed in chronic myeloid leukemia ( Ianniello et al, 2021 ), thymic epithelial tumors ( Iaiza et al, 2021 ), esophageal cancer ( Han et al, 2021 ), and prostate cancer ( Chen et al, 2021b ), suggesting a close relationship with malignant tumor development. Previous studies also suggested that METTL3 is significantly up-regulated in BC.…”