Abstract
The abnormal m6A modification caused by m6A modulators is a common feature of various tumors; however, little is known about which m6A modulator plays the most important role in triple-negative breast cancer (TNBC). In this study, when analyzing the influence of m6A modulators (METTL3, METTL14, WTAP, FTO, and ALKBH5) on the prognosis of breast cancer, especially in TNBC using several on-line databases, methyltransferase-like 3 (METTL3) was found to have low expression in breast cancer, and was closely associated with short-distance-metastasis-free survival in TNBC. Further investigation showed that knockdown of METTL3 could enhance the ability of migration, invasion, and adhesion by decreasing m6A level in TNBC cell lines. Collagen type III alpha 1 chain (COL3A1) was identified and verified as a target gene of METTL3. METTL3 could down-regulate the expression of COL3A1 by increasing its m6A methylation, ultimately inhibiting the metastasis of TNBC cells. Finally, with immunohistochemistry staining in breast cancer tissues, it was proved that METTL3 expression was negatively correlated with COL3A1 in TNBC, but not in non-TNBC. This study demonstrated the potential mechanism of m6A modification in metastasis and provided potential targets for treatment in TNBC.
Highlights
Breast cancer, the most common cancer in women, poses a serious threat to the health of women [1]
To investigate which m6A modulator plays an important role in breast cancer, especially in triple-negative breast cancer (TNBC), the mRNA expressions of m6A methyltransferases (METTL3, methyltransferase-like 14 (METTL14), and Wilms tumor 1-associated protein (WTAP)) and demethylases (FTO and AlkB family member 5 (ALKBH5)) were first compared between breast cancer tissues and normal breast tissues using the RNA sequencing expression data in GEPIA on-line database
The analysis result indicated that no significant difference of distance-metastasis-free survival (DMFS) was obtained between the patients with all three modulators in high-expression groups and low-expression groups (Figure 1B); for the TNBC patients, no significant difference was found between the DMFS of the METTL14 high-expression group and low-expression group, the DMFS of methyltransferase-like 3 (METTL3) high expression group was shown to be longer than that in the METTL3 lowexpression group, whereas the DMFS of the FTO high-expression group was shorter than that of the FTO low-expression group, indicating that METTL3 is a protective factor, but FTO is a risk factor for DMFS of TNBC (Figure 1C)
Summary
The most common cancer in women, poses a serious threat to the health of women [1]. The methyltransferase METTL14 can inhibit tumor metastasis in HCC by positively regulating the m6A level of DGCR8 and promoting the binding of DGCR8 to pri-miRNAs [6]; the demethylase FTO can promote cell proliferation via down-regulating the m6A level of USP7 in advanced non-small cell lung cancer, indicating the repression role of m6A in cancer development [7], other studies obtained contradictory results wherein METTL3 could promote the proliferation of prostate cancer cell via enhancing the m6A level of GLI15 [8]; ALKBH5 was found to be able to inhibit pancreatic cancer metastasis by down-regulating KCNK15-AS1, suggesting that m6A modification of RNA plays an oncogenic role in cancer [9] It seems that an m6A modulator might play both promotional, and inhibitory roles in different types of cancers by regulating different specific target genes. The underlying role and epigenetic regulation of m6A modulators in breast cancer, especially in TNBC, still needs to be investigated
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