MEX3A-mediated super-enhancer RNA m6A methylation promotes aggressiveness of breast cancer via regulating RBM15B/IGF2BP3/KMT2C signaling

N6-methyladenosine (m6A) modification is implicated in the tumorigenesis of breast Cancer. This study aims to investigate super-enhancer RNA (seRNA) m6A modification in breast Cancer and unveil the molecular mechanisms underlying seRNA m6A and H3K4me1 modification. Gene expression is analyzed by reverse transcription-quantitative PCR, Western blot, immunofluorescence, and immunohistochemistry. Co-localization between Insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) and lysine methyltransferase 2C (KMT2C) is determined using fluorescence in situ hybridization assay. RNA binding motif protein 15B (RBM15B)-binding levels of seRNA m6A are analyzed by methylated RNA immunoprecipitation assay. The mex-3 RNA binding family member A (MEX3A)-RBM15B interaction is determined using co-immunoprecipitation assay. Cellular functions are determined using Cell Counting Kit-8, colony formation, and transwell assays. In vivo assays are performed to further verify the role of MEX3A in breast Cancer. The results show that MEX3A is overexpressed in breast Cancer and promotes seRNA m6A methylation formation. Interestingly, MEX3A deficiency inhibits the proliferation and metastasis of breast Cancer in vivo and in vitro. Increased seRNA m6A modification is recognized by the reader protein IGF2BP3. MEX3A interacts with RBM15B/IGF2BP3 to maintain KMT2C mRNA expression and stability, enhancing seRNA m6A modification. Furthermore, RBM15B/IGF2BP3 recruits the H3K4 methyltransferase KMT2C to promote H3K4me1 formation. KMT2C overexpression promotes breast Cancer proliferation and metastasis. In summary, MEX3A promotes the aggressiveness of breast Cancer via regulating the seRNA m6A/RBM15B/IGF2BP3/KMT2C axis. Therefore, targeting the MEX3A/seRNA m6A/RBM15B-IGF2BP3/KMT2C axis may be a therapeutic target for breast Cancer.

Breast cancer; MEX3A; Metastasis; RBM15B; seRNA m6A.