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Suppression of MBD2 alternative splicing promotes breast cancer metastasis by activating FZD1 under hypoxia

ABSTRACT: Metastasis is responsible for the majority of breast cancer (BrCa) deaths; however, the underlying mechanisms remain largely elusive. Here, we report that suppression of MBD2 alternative splicing under hypoxia, which favors the production of MBD2a, facilitates BrCa metastasis. Specifically, we found that MBD2a promotes, whereas its less-known short form MBD2c suppresses metastasis. We elucidate that HIF-1 activation under hypoxia facilitates MBD2a production via repression of SRSF2-mediated alternative splicing and, as a result, the elevated MBD2a outcompetes MBD2c for binding to the promoter CpG islands to activate the expression of FZD1, thereby promoting EMT and metastasis. Strikingly, clinical data reveals significantly correlated expression pattern of MBD2a and MBD2c with the invasiveness of malignancy, indicating the opposing roles for MBD2 splicing variants in regulating human BrCa metastasis. Thus, our findings establish a novel link between MBD2 switching and tumor metastasis, and provide promising therapeutic strategy and predictive biomarkers for hypoxia-driven BrCa metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151952 | GEO | 2021/02/01

REPOSITORIES: GEO

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Alternative Splicing of MBD2 Supports Self-Renewal in Human Pluripotent Stem Cells [HG-U133_Plus_2]

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