Decourtye-Espiard Lyvianne, Bougen-Zhukov Nicola, Godwin Tanis, Brew Tom, Schulpen Emily, Black Michael A, Guilford Parry
Cancer Genetics Laboratory, Centre for Translational Cancer Research (Te Aho Matatū), Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand.
Cancers (Basel). 2021 Dec 30;14(1):175. doi: 10.3390/cancers14010175.
Inactivating germline mutations in the gene (encoding the E-cadherin protein) are the genetic hallmark of hereditary diffuse gastric cancer (HDGC), and somatic 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 expression. 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. -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 and deletions. However, the deletion of largely abrogated the sensitivity of the -null organoids to pracinostat and mocetinostat. Finally, entinostat enhanced expression in heterozygous 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 -deficient cancers.
基因（编码E-钙黏蛋白）中的种系失活突变是遗传性弥漫性胃癌（HDGC）的遗传标志，而体细胞突变是散发性弥漫性胃癌（DGC）和小叶性乳腺癌（LBC）发生过程中的早期事件。在本研究中，测试了组蛋白去乙酰化酶（HDAC）抑制剂优先抑制缺乏该基因表达的人细胞系（MCF10A和NCI-N87）和小鼠类器官生长的能力。该基因缺失的乳腺和胃细胞比野生型细胞对泛HDAC抑制剂恩替诺特、普拉西诺特、莫西诺特和伏立诺他更敏感，生长抑制增强，部分原因是细胞凋亡增加。该基因缺失的细胞对更多类特异性HDAC抑制剂也敏感，但与泛抑制剂相比，这些作用对遗传背景的影响较小。在同时存在该基因和另一个基因缺失的胃类器官中也观察到对恩替诺特的敏感性增加。然而，该基因的缺失在很大程度上消除了该基因缺失的类器官对普拉西诺特和莫西诺特的敏感性。最后，恩替诺特增强了杂合该基因缺失的小鼠类器官中的该基因表达。总之，恩替诺特是一种有前途的用于HDGC化学预防和/或治疗的药物，对散发性该基因缺陷癌症的治疗可能也有益。
