Epigenetic modulation of spca2 reverses epithelial to mesenchymal transition in breast cancer cells

Monish Ram Makena, Myungjun Ko, Donna Kimberly Dang, Rajini Rao

Research output: Contribution to journalArticlepeer-review

Abstract

The secretory pathway Ca2+-ATPase SPCA2 is a tumor suppressor in triple receptor negative breast cancer (TNBC), a highly aggressive molecular subtype that lacks tailored treatment options. Low expression of SPCA2 in TNBC confers poor survival prognosis in patients. Previous work has established that re-introducing SPCA2 to TNBC cells restores basal Ca2+ signaling, represses mesenchymal gene expression, mitigates tumor migration in vitro and metastasis in vivo. In this study, we examined the effect of histone deacetylase inhibitors (HDACi) in TNBC cell lines. We show that the pan-HDACi vorinostat and the class I HDACi romidepsin induce dose-dependent upregulation of SPCA2 transcript with concurrent downregulation of mesenchymal markers and tumor cell migration characteristic of epithelial phenotype. Silencing SPCA2 abolished the ability of HDACi to reverse epithelial to mesenchymal transition (EMT). Independent of ATPase activity, SPCA2 elevated resting Ca2+ levels to activate downstream components of non-canonical Wnt/Ca2+ signaling. HDACi treatment led to SPCA2-dependent phosphorylation of CAMKII and β-catenin, turning Wnt signaling off. We conclude that SPCA2 mediates the efficacy of HDACi in reversing EMT in TNBC by a novel mode of non-canonical Wnt/Ca2+ signaling. Our findings provide incen-tive for screening epigenetic modulators that exploit Ca2+ signaling pathways to reverse EMT in breast tumors.

Original languageEnglish (US)
Article number259
Pages (from-to)1-18
Number of pages18
JournalCancers
Volume13
Issue number2
DOIs
StatePublished - Jan 2 2021

Keywords

  • Ca-ATPase
  • EMT
  • HDAC inhibitors
  • Ro-midepsin
  • SICE
  • TNBC
  • Vimentin
  • Vorinostat
  • WNT signaling

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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