Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells
The secretory pathway Ca<sup>2+</sup>-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 wo...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/2/259 |
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| author | Monish Ram Makena Myungjun Ko Donna Kimberly Dang Rajini Rao |
| author_facet | Monish Ram Makena Myungjun Ko Donna Kimberly Dang Rajini Rao |
| author_sort | Monish Ram Makena |
| collection | DOAJ |
| description | The secretory pathway Ca<sup>2+</sup>-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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> levels to activate downstream components of non-canonical Wnt/Ca<sup>2+</sup> 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/Ca<sup>2+</sup> signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca<sup>2+</sup> signaling pathways to reverse EMT in breast tumors. |
| first_indexed | 2024-03-09T05:05:10Z |
| format | Article |
| id | doaj.art-81fb78117d284e8e859e57d5acece305 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T05:05:10Z |
| publishDate | 2021-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-81fb78117d284e8e859e57d5acece3052023-12-03T12:55:35ZengMDPI AGCancers2072-66942021-01-0113225910.3390/cancers13020259Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer CellsMonish Ram Makena0Myungjun Ko1Donna Kimberly Dang2Rajini Rao3Department of Physiology, Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, MD 21205, USADepartment of Physiology, Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, MD 21205, USADepartment of Physiology, Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, MD 21205, USADepartment of Physiology, Johns Hopkins University School of Medicine, 725 N. Wolfe St, Baltimore, MD 21205, USAThe secretory pathway Ca<sup>2+</sup>-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 Ca<sup>2+</sup> 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 Ca<sup>2+</sup> levels to activate downstream components of non-canonical Wnt/Ca<sup>2+</sup> 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/Ca<sup>2+</sup> signaling. Our findings provide incentive for screening epigenetic modulators that exploit Ca<sup>2+</sup> signaling pathways to reverse EMT in breast tumors.https://www.mdpi.com/2072-6694/13/2/259TNBCCa<sup>2+</sup>-ATPaseSICEHDAC inhibitorsEMTWNT signaling |
| spellingShingle | Monish Ram Makena Myungjun Ko Donna Kimberly Dang Rajini Rao Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells Cancers TNBC Ca<sup>2+</sup>-ATPase SICE HDAC inhibitors EMT WNT signaling |
| title | Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells |
| title_full | Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells |
| title_fullStr | Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells |
| title_full_unstemmed | Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells |
| title_short | Epigenetic Modulation of SPCA2 Reverses Epithelial to Mesenchymal Transition in Breast Cancer Cells |
| title_sort | epigenetic modulation of spca2 reverses epithelial to mesenchymal transition in breast cancer cells |
| topic | TNBC Ca<sup>2+</sup>-ATPase SICE HDAC inhibitors EMT WNT signaling |
| url | https://www.mdpi.com/2072-6694/13/2/259 |
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