METTL3 regulates m6A in endometrioid epithelial ovarian cancer independently of METTl14 and WTAP

Abstract

N6‐methyladenosine (m6A) RNA methylation, one of the common RNA modifications, has been determined to execute crucial functions in tumorigenesis and cancer development. The m6A “writers” including methyltransferase like 3 (METTL3), METTL14, and Wilms tumor 1‐associated protein (WTAP) contribute to the m6A modification process initiation. However, the coordination of m6A methyltransferase complex is not fully understood in endometrioid epithelial ovarian cancer (EEOC). In this study, mRNA and protein levels of METTL3, METTL14, and WTAP were detected in 33 EEOC cases using quantitative polymerase chain reaction (qPCR), immunohistochemistry, and western blot analysis. The overall m6A methylation was detected by dot plot. The METTL3 expression and overall m6A level were elevated in EEOC tissues, while the expressions of METTL14 and WTAP have no significant difference in EEOC compared to the adjacent tissues. The expression of METTL3 was an independent factor that correlated with poor malignancy and survival of EEOC patients. Moreover, METTL3 knockdown in TOV‐112D and CRL‐11731D cells weakened the capability of cell proliferation and migration, and promoted cell apoptosis compared to negative control and cells with WTAP or METTL14 knockdown using CCK‐8 assay, transwell assay, wound healing assay, and TUNEL assay. Furthermore, METTL3 knockdown also reduced m6A enrichment of the genes associated with ovarian cancer including EIF3C, AXL, CSF‐1, FZD10 in TOV‐112D, and CRL‐11731D cells by RIP‐qPCR assay. Taken together, the high expressed METTL3 indicated poor malignancy and survival of EEOC via modulating the aberrant m6A RNA methylation. METTL3‐mediated m6A modification, independent of WTAP and METTL14, was considered as a novel mechanism underlying m6A modulation and a potential therapeutic target of EEOC.

Identification and validation of lncRNAs involved in m6A regulation for patients with ovarian cancer

“…IGF2BP1 (reader) was demonstrated to augment the translation of serum response factor through m6A modification [10]. METTL3 (writer) can regulate m6A methylation and thus regulate the malignancy of OC [11][12][13][14]. It has been proven that FTO (eraser) regulates PDE4B and PDE1C by m6A and thus plays a tumor suppressor function in OC [15].…”

RNA m6A methylation regulators in ovarian cancer

“…In OC cell lines, after METTL3 was knocked out, the proliferation, invasion and migration of cells in the METTL3-deficient group were significantly reduced, and cell apoptosis was accelerated. At the same time, METTL3 effectively downregulated the overall m6A level, suggesting that METTL3 plays an oncogenic part in ovarian cancer [107].…”

“…As one of the "writers", METTL3 participated in the initiation of the m6A modification process. Ma et al indicated that METTL3 expresses highly is one of the reasons for the abnormally elevated m6A level, which is associated with degree of malignancy and survival time of OC patients [107]. Their study found that the overall m6A level of OC is appreciably higher than in neighbouring tissues and that METTL3 was strongly expressed in OC compared to METTL14 or WTAP.…”

RNA Methylations in Cardiovascular Diseases, Molecular Structure, Biological Functions and Regulatory Roles in Cardiovascular Diseases

“…The METTL3 can inhibit the metastasis of breast cancer cells by increasing the methylation level of m6A and down-regulating the expression of COL3A1 ( Shi et al, 2020b ). The METTL3 regulates the m6A modification in endometrioid epithelial ovarian cancer independently of METTL14 and WTAP ( Ma et al, 2020 ). Furthermore, The METTL3 promotes the development and progression of thyroid cancer by regulating the m6A methylation on TCF1 ( Wang et al, 2020b ).…”