Figure 7.

Epigenetic modulation of SPCA2 in TNBC reverses EMT through Ca²⁺/Wnt signaling. Breast cancer cells undergo reversible transitions between mesenchymal state, characterized by low cytosolic Ca²⁺ (blue) and detached junctional protein E-cadherin (yellow bars), and epithelial state, characterized by higher resting Ca²⁺ (red), attachment to the basement membrane (gray), and cell-cell junctions (yellow). Previous work showed that ectopic expression of SPCA2 in TNBC cells increases cytosolic Ca²⁺ and E-cadherin expression to promote epithelial phenotypes. In this study, we show that HDAC inhibitors (vorinostat and romidepsin) increase histone acetylation leading to increased SPCA2 transcription, which in turn elevates resting Ca²⁺ by activation of store-independent Ca²⁺ entry. Ca²⁺ activates non-canonical Wnt signaling by phosphorylating CAMKII and β-catenin, turning Wnt OFF. This blocks EMT and promotes MET.