Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Triple-negative breast cancer (TNBC) is aggressive and lacks targeted treatments.
• Secretory pathway Ca2+-ATPase 2 (SPCA2) acts as a tumor suppressor in TNBC, with low expression correlating to poor patient survival.
• Restoring SPCA2 in TNBC cells normalizes calcium signaling, reduces mesenchymal gene expression, and inhibits tumor cell migration and metastasis.

Purpose of the Study:

• To investigate the effects of histone deacetylase inhibitors (HDACi) on SPCA2 expression and function in TNBC.
• To elucidate the role of SPCA2 in mediating the anti-cancer effects of HDACi.

Main Methods:

• Treatment of TNBC cell lines with vorinostat (pan-HDACi) and romidepsin (class I HDACi).
• Analysis of SPCA2 transcript levels, mesenchymal markers, and tumor cell migration.
• Assessment of SPCA2's role in epithelial-to-mesenchymal transition (EMT) reversal via gene silencing.
• Investigation of SPCA2's impact on non-canonical Wnt/Ca2+ signaling, including CAMKII and beta-catenin phosphorylation.

Main Results:

• Vorinostat and romidepsin induced dose-dependent increases in SPCA2 transcript levels.
• HDACi treatment led to decreased mesenchymal markers and reduced tumor cell migration, characteristic of an epithelial phenotype.
• Silencing SPCA2 abrogated the ability of HDACi to reverse EMT.
• SPCA2 elevated resting Ca2+ levels, activating non-canonical Wnt/Ca2+ signaling, and HDACi treatment promoted SPCA2-dependent CAMKII and beta-catenin phosphorylation.

Conclusions:

• SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC through a novel non-canonical Wnt/Ca2+ signaling pathway.
• HDACi promote SPCA2-dependent inactivation of Wnt signaling, contributing to the reversal of EMT.
• These findings suggest that epigenetic modulators targeting Ca2+ signaling pathways could be a promising therapeutic strategy for TNBC.