Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer

Abstract

ObjectivesRecently, an increasing number of studies have revealed that N6-methyladenosine (m6A) functions as a significant post-transcriptional modification which plays a critical role in the occurrence and progression of enriched tumors by regulating coding and non-coding RNA biogenesis. However, the biological function of m6A in breast cancer remains largely unclear.Materials and MethodsIn this study, we used a series of bioinformatic databases and tools to jointly analyze the expression of m6A methylation transferases (METTL3, METTL14, WTAP, RBM15, RBM15B and ZC3H13) and investigate the prognostic value of METTL14 and ZC3H13 in breast cancer. Besides, we analyzed the downstream carcinogenic molecular mechanisms related to METTL14 and ZC3H13 and their relationship with immune infiltration in breast tumor tissues.ResultsThe results showed that METTL14 and ZC3H13 were the down-regulated m6A methylation transferases in breast cancer. Survival outcome analysis suggested that abnormally low expression of METTL14 and ZC3H13 could predict unfavorable prognosis in four breast cancer subtypes. Moreover, their down-regulation was associated with ER-, PR- and triple-negative breast cancer patients, as well as tumor progression (increased Scarff, Bloom and Richardson grade status and Nottingham Prognostic Index classification). Co-expression analysis revealed that METTL14 and ZC3H13 had a strong positive correlation with APC, an antagonist of the Wnt signaling pathway, indicating they might cooperate in regulating proliferation, invasion, and metastasis of tumor cells. METTL14, ZC3H13, and APC expression levels had significant positive correlation with infiltrating levels of CD4+ T cells, CD8+ T cells, neutrophils, macrophages, and dendritic cells, and negative correlation with Treg cells in breast cancer.ConclusionsThis study demonstrated that down-regulation of METTL14 and ZC3H13 which act as two tumor suppressor genes was found in breast cancer and predicted poor prognosis. Their abnormal expression promoted breast cancer invasion by affecting pathways related to tumor progression and mediating immunosuppression.

Roles of RNA Methylation on Tumor Immunity and Clinical Implications

“…The study puts forward a scientific hypothesis: the low expression of METTL14 and ZC3H13 leads to the decrease of Adenomatous polyposis coli (APC) mRNA methylation, which in turn reduces the stability of APC mRNA. The decrease of APC level leads to the abnormal activation of Wnt signal pathway which plays an important role in the regulation of tumor immune microenvironment and regulate the infiltration and activity of various types of T cells in tumor ( 118 ).…”

A comprehensive investigation of m6A regulators prognostic value and associated molecular pathways in breast invasive cancer

“…Our study indicated that high expression of VIRMA, METTL14, and RBM15B, and low expression of EIF3B, YTHDF1, and YTHDF3 is correlated with longer OS, and these genes could serve as markers to predict the prognosis of BIC (Figure 4). There are common and unique genes in the final set of identified genes as prognostic markers in our and the other cancer studies [63,75,79] which highlight the diverse roles of the m 6 A pathway genes in the progression of different human malignancies. To get more insights into the underlying mechanisms, the association of mutation frequency of the genes with prognostic value was examined and nine of the m 6 A pathway genes (METTL14, RBM15, WTAP, HNRNPA2B1, SRSF2, YTHDF1, YTHDF2, YTHDF3, and ALKBH5) were correlated with the prognosis of BIC (Figure S4).…”

“…Furthermore, expression level and function variation of m 6 A genes among the cancer types may imply the tumor type-specific roles of this pathway. As an example, METTL14 can act as a tumor-suppressor as in colorectal cancer [73], renal cell carcinoma [74] and breast cancer [75], or oncogene as in pancreatic cancer [76] which might be due to the target RNA composition specific to cancer types. Therefore, as performed in this study, analysis of these genes using the comprehensive datasets would be more informative to approximate the exact function of the genes across the possible multiple roles of m 6 A pathway components in investigated cancers.…”

Role of m6A in osteoporosis, arthritis and osteosarcoma (Review)

“…However, whether METTL14 exhibits methyltransferase activity after binding to additional factors remains unknown. METTL14 is also involved in the regulation of several tumour processes ( 67 , 68 ). For example, the METTL14-m6A-Notch1 pathway plays a critical role in bladder tumorigenesis and bladder tumour-initiating cells ( 69 ).…”

“…ZC3H13 plays a critical role in anchoring WTAP, Virilizer and Hakai in the nucleus to facilitate m6A methylation, and regulates mESC self-renewal ( 77 ). ZC3H13 also participates in the development and progression of different types of tumours ( 68 , 78 ). It has been reported that ZC3H13 expression is substantially downregulated in clear cell renal cell carcinoma tissues ( 79 ).…”