Hypoxia-Induced Suppression of Alternative Splicing of MBD2 Promotes Breast Cancer Metastasis via Activation of FZD1

Abstract Metastasis is responsible for the majority of breast cancer–related deaths, however, mechanisms underlying metastasis in this disease remain largely elusive. Here we report that under hypoxic conditions, alternative splicing MBD2 suppressed, favoring production MBD2a, which facilitates cancer metastasis. Specifically, MBD2a promoted, whereas its lesser known short form MBD2c suppressed Activation HIF1 hypoxia facilitated via repression SRSF2-mediated splicing. As a result, elevated outcompeted binding to promoter CpG islands activate expression FZD1, thereby promoting epithelial-to-mesenchymal transition and Strikingly, clinical data reveal significantly correlated with invasiveness malignancy, indicating opposing roles variants regulating human Collectively, our findings establish novel link between switching tumor provide promising therapeutic strategy predictive biomarkers hypoxia-driven Significance: This study defines relevance MBD2c, two products,