The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer

Abstract

Background Posttranscriptional modification of tumor-associated factors plays a pivotal role in breast cancer progression. However, the underlying mechanism remains unknown. M6A modifications in cancer cells are dynamic and reversible and have been found to impact tumor initiation and progression through various mechanisms. In this study, we explored the regulatory mechanism of breast cancer cell proliferation and metabolism through m6A methylation in the Hippo pathway. Methods A combination of MeRIP-seq, RNA-seq and metabolomics-seq was utilized to reveal a map of m6A modifications in breast cancer tissues and cells. We conducted RNA pull-down assays, RIP-qPCR, MeRIP-qPCR, and RNA stability analysis to identify the relationship between m6A proteins and LATS1 in m6A regulation in breast cancer cells. The expression and biological functions of m6A proteins were confirmed in breast cancer cells in vitro and in vivo. Furthermore, we investigated the phosphorylation levels and localization of YAP/TAZ to reveal that the activity of the Hippo pathway was affected by m6A regulation of LATS1 in breast cancer cells. Results We demonstrated that m6A regulation plays an important role in proliferation and glycolytic metabolism in breast cancer through the Hippo pathway factor, LATS1. METTL3 was identified as the m6A writer, with YTHDF2 as the reader protein of LATS1 mRNA, which plays a positive role in promoting both tumorigenesis and glycolysis in breast cancer. High levels of m6A modification were induced by METTL3 in LATS1 mRNA. YTHDF2 identified m6A sites in LATS1 mRNA and reduced its stability. Knockout of the protein expression of METTL3 or YTHDF2 increased the expression of LATS1 mRNA and suppressed breast cancer tumorigenesis by activating YAP/TAZ in the Hippo pathway. Conclusions In summary, we discovered that the METTL3-LATS1-YTHDF2 pathway plays an important role in the progression of breast cancer by activating YAP/TAZ in the Hippo pathway.

METTL3 as a novel diagnosis and treatment biomarker and its association with glycolysis, cuproptosis and ceRNA in oesophageal carcinoma

“…METTL3, an important RNA methyltransferase, plays a critical role in RNA modification, and its expression and catalysed RNA m6A modification are associated with the occurrence and progression of various human diseases 10–12,14 . Prior studies have demonstrated that METTL3 is overexpressed in various cancers and contributes to cancer progression and metastasis 21,46–55 . In this study, we further confirmed through multi‐data set analysis that the expression of METTL3 was significantly higher in tumour samples than in the control group.…”

“…[10][11][12]14 Prior studies have demonstrated that METTL3 is overexpressed in various cancers and contributes to cancer progression and metastasis. 21,[46][47][48][49][50][51][52][53][54][55] In this study, we further confirmed through multi-data set analysis that the expression of METTL3 was significantly higher in tumour samples than in the control group. ROC results indicated that its expression the expression of ER target genes and limits the growth of breast cancer cells.…”

METTL3‐mediated the m6A modification of SF3B4 facilitates the development of non‐small cell lung cancer by enhancing LSM4 expression

“…More and more studies have shown that METTL3 regulates mRNA stability through m6A methylation, thereby mediating cancer progression. For example, METTL3 decreased LATS1 mRNA expression in a m6A‐dependent manner, thereby accelerating breast cancer tumorigenesis and glycolysis 21 . Also, METTL3 promoted pancreatic cancer cell proliferation and stemness by increasing ID2 mRNA stability through m6A modification 22 .…”

Glucose dysregulation promotes oncogenesis in human bladder cancer by regulating autophagy and YAP1/TAZ expression

“…It is known that upstream regulators of the Hippo pathway, such as mammalian Ste20‐like kinases 1/2 (MST1/2) and LATS1/2, converge at the downstream effectors, YAP1 and TAZ 41 . Previous studies have also demonstrated the oncogenic roles of MST1/2 42 and LATS1/2 43 in human tumours, including proliferation, apoptosis, and glucose metabolism. Furthermore, some other common kinases, such as epidermal growth factor receptor (EGFR) kinase, have also been correlated with autophagy 44 or glucose metabolism 45 in human diseases.…”