E-Cadherin-Deficient Epithelial Cells Are Sensitive to HDAC Inhibitors

SIMPLE SUMMARY: Inactivating mutations in the CDH1 gene cause the cancer syndrome hereditary diffuse gastric cancer and are also frequent in sporadic diffuse gastric and lobular breast cancers. This research aimed to test whether cancers with CDH1 mutations have heightened sensitivity to histone deacetylase (HDAC) inhibitors. The impact of these drugs was tested on several gastric and breast preclinical models with and without CDH1 mutations. One HDAC inhibitor, entinostat, showed a strong inhibitory effect on each of the models with CDH1 mutations. This study highlighted the potential beneficial impact of entinostat for the chemoprevention and/or treatment of gastric and breast cancers carrying CDH1 mutations. 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.