YTHDF1 promotes breast cancer progression by facilitating FOXM1 translation in an m6A-dependent manner

Abstract

Background N6-methyladenosine (m6A) is the most common post-transcriptional modification at the RNA level. However, the exact molecular mechanisms of m6A epigenetic regulation in breast cancer remain largely unknown and need to be fully elucidated. Methods The integrating bioinformatics analyses were used to screen clinical relevance and dysregulated m6A “reader” protein YTHDF1 in breast cancer from TCGA databases, which was further validated in a cohort of clinical specimens. Furthermore, functional experiments such as the CCK-8 assay, EdU assay, wound healing assay, transwell invasion assay and cell cycle assay were used to determine the biological role of YTHDF1 in breast cancer. RIP, m6A-IP, and CLIP assays were used to find the target of YTHDF1 and further verification by RT-qPCR, western blot, polysome profiling assay. The protein–protein interaction between YTHDF1 and FOXM1 was detected via co-immunoprecipitation. Results Our study showed that YTHDF1 was overexpressed in breast cancer cells and clinical tissues specimens. At the same time, the high expression level of YTHDF1 was positively correlated with tumor size, lymph node invasion, and distant metastasis in breast cancer patients. YTHDF1 depletion repressed the proliferation, invasion and epithelial-mesenchymal transformation (EMT) and induced G0/G1 phase cell cycle arrest of breast cancer cells in vitro and in vivo. We also demonstrated that FOXM1 is a target of YTHDF1. Through recognizing and binding to the m6A-modified mRNA of FOXM1, YTHDF1 accelerated the translation process of FOXM1 and promoted breast cancer metastasis. Whereas overexpression of FOXM1 in breast cancer cells partially counteracted the tumor suppressed effects caused by YTHDF1 silence, which further verified the regulatory relationship between YTHDF1 and FOXM1. Conclusion Our study reveals a novel YTHDF1/FOXM1 regulatory pathway that contributes to metastasis and progression of breast cancer, suggesting that YTHDF1 might be applied as a potential biomarker and therapeutic target. That also advances our understanding of the tumorigenesis for breast cancer from m6A epigenetic regulation.

Mutual regulation between N6-methyladenosine (m6A) modification and circular RNAs in cancer: impacts on therapeutic resistance

“…Besides, Yu et al analyzed the expression profile of m6A-related regulators acquired from TCGA database, and revealed that upregulated IGF2BP2 in head and neck squamous cell carcinoma (HNSCC) helped stabilize Slug mRNA, thus facilitating MET process and lymphatic metastasis of HNSCC [ 119 ]. Consistently, EMT regulated by m6A has also been observed in other cancers, including GC and breast cancer [ 120 , 121 ]. Taken together, these studies imply that m6A modification may contribute to therapeutic resistance by influencing EMT process.…”

The Key Role of RNA Modification in Breast Cancer

“…DF1 promotes mRNA translation, DF2 promotes mRNA degradation, and DF3 promotes translation and degradation ( Zaccara and Jaffrey, 2020 ). YTHDF1 and YTHDF3 were also found to overexpress in breast cancer ( Chen et al, 2022 ; Lin et al, 2022 ). IGF2BP 2/3 and YTHDC2 were highly expressed in basal-like breast cancer ( Yang et al, 2020 ).…”

The Role of m6A RNA Methylation in Cancer: Implication for Nature Products Anti-Cancer Research

“…YTHDF1 and YTHDF3 are highly expressed in BCa patients and with poor prognosis, which can enhance the expression of related genes, such as FOXM1, ST6GALNAC5, GJA1, EGFR, VEGFRA, etc., and promote the metastasis, invasion and angiogenesis of BCa cells ( Chang et al, 2020 ; Chen et al, 2022 ).…”