E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors
Inactivating germline mutations in the <i>CDH1</i> gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic <i>CDH1</i> mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and...
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| Format: | Article |
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MDPI AG
2021-12-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/1/175 |
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| author | Lyvianne Decourtye-Espiard Nicola Bougen-Zhukov Tanis Godwin Tom Brew Emily Schulpen Michael A. Black Parry Guilford |
| author_facet | Lyvianne Decourtye-Espiard Nicola Bougen-Zhukov Tanis Godwin Tom Brew Emily Schulpen Michael A. Black Parry Guilford |
| author_sort | Lyvianne Decourtye-Espiard |
| collection | DOAJ |
| description | Inactivating germline mutations in the <i>CDH1</i> gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic <i>CDH1</i> mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In this study, histone deacetylase (HDAC) inhibitors were tested for their ability to preferentially inhibit the growth of human cell lines (MCF10A and NCI-N87) and murine organoids lacking <i>CDH1</i> expression. <i>CDH1<sup>−/−</sup></i> breast and gastric cells were more sensitive to the pan-HDAC inhibitors entinostat, pracinostat, mocetinostat and vorinostat than wild-type cells, with an elevated growth inhibition that was, in part, attributable to increased apoptosis. <i>CDH1</i>-null cells were also sensitive to more class-specific HDAC inhibitors, but compared to the pan-inhibitors, these effects were less robust to genetic background. Increased sensitivity to entinostat was also observed in gastric organoids with both <i>Cdh1</i> and <i>Tp53</i> deletions. However, the deletion of <i>Tp53</i> largely abrogated the sensitivity of the <i>Cdh1</i>-null organoids to pracinostat and mocetinostat. Finally, entinostat enhanced <i>Cdh1</i> expression in heterozygous <i>Cdh1<sup>+/−</sup></i> murine organoids. In conclusion, entinostat is a promising drug for the chemoprevention and/or treatment of HDGC and may also be beneficial for the treatment of sporadic <i>CDH1</i>-deficient cancers. |
| first_indexed | 2024-03-10T03:47:35Z |
| format | Article |
| id | doaj.art-b81d12684e0249d6a9afb250262d97e7 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T03:47:35Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-b81d12684e0249d6a9afb250262d97e72023-11-23T11:17:17ZengMDPI AGCancers2072-66942021-12-0114117510.3390/cancers14010175E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC InhibitorsLyvianne Decourtye-Espiard0Nicola Bougen-Zhukov1Tanis Godwin2Tom Brew3Emily Schulpen4Michael A. Black5Parry Guilford6Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin 9016, New ZealandCancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin 9016, New ZealandCancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin 9016, New ZealandCancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin 9016, New ZealandCancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin 9016, New ZealandCancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin 9016, New ZealandCancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin 9016, New ZealandInactivating germline mutations in the <i>CDH1</i> gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic <i>CDH1</i> mutations are an early event in the development of sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC). In this study, histone deacetylase (HDAC) inhibitors were tested for their ability to preferentially inhibit the growth of human cell lines (MCF10A and NCI-N87) and murine organoids lacking <i>CDH1</i> expression. <i>CDH1<sup>−/−</sup></i> breast and gastric cells were more sensitive to the pan-HDAC inhibitors entinostat, pracinostat, mocetinostat and vorinostat than wild-type cells, with an elevated growth inhibition that was, in part, attributable to increased apoptosis. <i>CDH1</i>-null cells were also sensitive to more class-specific HDAC inhibitors, but compared to the pan-inhibitors, these effects were less robust to genetic background. Increased sensitivity to entinostat was also observed in gastric organoids with both <i>Cdh1</i> and <i>Tp53</i> deletions. However, the deletion of <i>Tp53</i> largely abrogated the sensitivity of the <i>Cdh1</i>-null organoids to pracinostat and mocetinostat. Finally, entinostat enhanced <i>Cdh1</i> expression in heterozygous <i>Cdh1<sup>+/−</sup></i> murine organoids. In conclusion, entinostat is a promising drug for the chemoprevention and/or treatment of HDGC and may also be beneficial for the treatment of sporadic <i>CDH1</i>-deficient cancers.https://www.mdpi.com/2072-6694/14/1/175HDGC<i>CDH1</i>E-cadherinHDAC inhibitorssynthetic lethality |
| spellingShingle | Lyvianne Decourtye-Espiard Nicola Bougen-Zhukov Tanis Godwin Tom Brew Emily Schulpen Michael A. Black Parry Guilford E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors Cancers HDGC <i>CDH1</i> E-cadherin HDAC inhibitors synthetic lethality |
| title | E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors |
| title_full | E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors |
| title_fullStr | E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors |
| title_full_unstemmed | E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors |
| title_short | E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors |
| title_sort | e cadherin deficient epithelial cells are sensitive to hdac inhibitors |
| topic | HDGC <i>CDH1</i> E-cadherin HDAC inhibitors synthetic lethality |
| url | https://www.mdpi.com/2072-6694/14/1/175 |
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