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Hypoxa-actived XBP1s recruits HDAC2-EZH2 to engage epigenetic suppression of DNp63 expression and promotes breast cacner metastasis independent HIF1a

ABSTRACT: Hypoxia is a hallmark of cancer development. However, the molecular mechanisms by which hypoxia promotes tumor metastasis are not fully understood. In this study, we demonstrate that hypoxia promotes breast cancer metastasis through suppression of ΔNp63α-dependent in a HIF1α-independent manner. We show that hypoxia activates unfolded protein response (UPR) to elevate XBP1s, which in turn forms stable repressor protein complexes with HDAC2 and EZH2 in suppression of ΔNp63α. Notably, while H3K27ac is predominantly presented in the ΔNp63 promoter under normoxia, it is switched to H3K27me3 under hypoxia. We show that XBP1s binds to the ΔNp63 promoter to recruit HDAC2 and EZH2 in facilitating the H3K27ac-H3K27me3 switch. Knockdown or pharmacological inhibition of either HDAC2 or EZH2 leads to increased H3K27ac concomitant with reduced H3K27me3, which effectively restores ΔNp63α expression suppressed by hypoxia, resulting in inhibition of cell migration. Clinical analyses reveal that reduced p63 expression is correlated with the elevated expression of XBP1, HDAC2, or EZH2, and is associated with poor overall survival in human breast cancer patients. Together, these results indicate that hypoxia-activated XBP1s modulates the epigenetic program in suppression of ΔNp63α to promote breast cancer metastasis independent of HIF1α and provides a molecule basis for targeting the XBP1s/HDAC2/EZH2-ΔNp63α axis as a putative strategy in the treatment of breast cancer metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253833 | GEO | 2024/01/24

REPOSITORIES: GEO

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