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E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors
Lyvianne Decourtye-Espiard1, Nicola Bougen-Zhukov1, Tanis Godwin1
1Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand.
Abstract:
Inactivating germline mutations in the CDH1 gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic CDH1 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 CDH1 expression. CDH1 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. CDH1-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 Cdh1 and Tp53 deletions. However, the deletion of Tp53 largely abrogated the sensitivity of the Cdh1-null organoids to pracinostat and mocetinostat. Finally, entinostat enhanced Cdh1 expression in heterozygous Cdh1 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 CDH1-deficient cancers.
Insights
Histone deacetylase (HDAC) inhibitors, particularly entinostat, show promise in treating cancers with CDH1 gene mutations. These drugs inhibit tumor growth by increasing apoptosis in CDH1-deficient cells.
Area of Science:
- Cancer Biology
- Genetics
- Pharmacology
Background:
- Germline CDH1 mutations define hereditary diffuse gastric cancer (HDGC).
- Somatic CDH1 mutations are early events in sporadic diffuse gastric cancer (DGC) and lobular breast cancer (LBC).
- CDH1 encodes the E-cadherin protein, crucial for cell adhesion.
Purpose of the Study:
- To investigate the efficacy of histone deacetylase (HDAC) inhibitors in targeting cancer cells with deficient CDH1 expression.
- To evaluate the potential of HDAC inhibitors for chemoprevention and treatment of CDH1-deficient cancers.
Main Methods:
- Testing HDAC inhibitors (entinostat, pracinostat, mocetinostat, vorinostat) on human cell lines (MCF10A, NCI-N87) and murine organoids lacking CDH1.
- Assessing cell growth inhibition, apoptosis, and effects of TP53 deletion.
- Examining CDH1 expression changes in response to entinostat.
Main Results:
- CDH1-deficient breast and gastric cancer cells showed increased sensitivity to pan-HDAC inhibitors, leading to greater growth inhibition and apoptosis.
- While CDH1-null cells responded to class-specific HDAC inhibitors, pan-inhibitors were more robust across different genetic backgrounds.
- Entinostat demonstrated efficacy in gastric organoids with combined CDH1 and TP53 deletions, unlike other tested inhibitors.
- Entinostat treatment increased CDH1 expression in heterozygous CDH1 murine organoids.
Conclusions:
- Entinostat is a potential therapeutic agent for hereditary diffuse gastric cancer (HDGC) and sporadic CDH1-deficient cancers.
- HDAC inhibitors offer a targeted approach for cancers characterized by CDH1 loss.
- Further research into entinostat's role in cancer chemoprevention and treatment is warranted.
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