Metformin exhibits antiproliferation activity in breast cancer via miR-483-3p/METTL3/m6A/p21 pathway

Abstract

Evidence suggests that metformin might be a potential candidate for breast cancer treatment. Yet, its relevant molecular mechanisms remain to be fully investigated. We found that metformin could suppress the N6-methyladenosine (m6A) level in breast cancer cells significantly. The latter has an essential role in breast cancer progression and is newly considered as a therapeutic target. In this study, we measured the m6A level by m6A colorimetric analysis and dot blot assay. We then performed qRT-PCR, western blot, MeRIP, dual-luciferase reporter assay, and others to explore the m6A-dependent pathway associated with metformin. In vivo effect of metformin was investigated using a mouse tumorigenicity model. In addition, breast cancer and normal tissues were used to determine the role of METTL3 in breast cancer. Metformin could reduce the m6A level via decreasing METTL3 expression mediated by miR-483-3p in breast cancer. METTL3 is known to be able to promote breast cancer cell proliferation by regulating the p21 expression by an m6A-dependent manner. Metformin can take p21 as the main target to inhibit such effect. To specify, this study exhibited that metformin can inhibit breast cancer cell proliferation through the pathway miR-483-3p/METTL3/m6A/p21. Our findings suggest that METTL3 may be considered as a potential therapeutic target of metformin for breast cancer.

lncRNA MALAT1 participates in metformin inhibiting the proliferation of breast cancer cell

“…Besides the role of MALAT1 in metformin treatment, some other epigenetic regulations would also critical for the anti‐tumour effect of metformin. In fact, metformin regulating DNA methylation, RNA methylation and histone methylation has already documented 6‐8 . This study further discovered that the abundance of RBBP4, G9a, acH3K9 and acH3K18 were changed by metformin treatment, suggesting that there might be a crucial role of histone modifiers for metformin cancer therapy.…”

“…In recent years, metformin exhibits anticancer property in a variety of cancers, including breast cancer 3,5 . For example, metformin has been shown to inhibit cell proliferation via decreasing the N6‐methyladenosin (m6A) level in breast cancer 6 . It could also conquer the resistance to gemcitabine by reversing epithelial‐mesenchymal transition (EMT) progress via modulating DNA methylation of miR‐663 in pancreatic cancer 7 .…”

N6-Methyladenosine-Regulated mRNAs: Potential Prognostic Biomarkers for Patients With Lung Adenocarcinoma

“…m6A. The most frequent modification of eukaryotic mRNA, has recently been reported to correlate with the progression of various cancers (Cheng et al, 2021), but its role in LUAD is not yet clear. In this study, we characterized the transcriptome-wide m6A modification profile in LUAD tissues and analyzed the correlation between m6A modification and gene expression.…”

Understanding the roles of N6-methyladenosine writers, readers and erasers in breast cancer

“…Metformin, which was previously regarded as anti-diabetic medicine, is capable of inhibiting breast cancer cell proliferation by down-regulating the expression of METTL3. This study suggests that drug repurposing is a valuable approach for the screening of m 6 A inhibitors, due to the possibility that FDA approved medications may exert m 6 A regulatory functions [77] . Recently, the researchers developed small molecule inhibitors CS1 and CS2, which target m 6 A “eraser” FTO in cancer [78] .…”