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

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 175
Author(s):  
Lyvianne Decourtye-Espiard ◽  
Nicola Bougen-Zhukov ◽  
Tanis Godwin ◽  
Tom Brew ◽  
Emily Schulpen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Hdac Inhibitors ◽  
Early Event ◽  
Diffuse Gastric Cancer ◽  
Lobular Breast Cancer ◽  
Wild Type ◽  
Cdh1 Gene ◽  
Gene Encoding ◽  
Increased Sensitivity ◽  
E Cadherin

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.

scholarly journals Clinical spectrum and pleiotropic nature of CDH1 germline mutations

2019 ◽  
Vol 56 (4) ◽  
pp. 199-208 ◽  
Author(s):  
Joana Figueiredo ◽  
Soraia Melo ◽  
Patrícia Carneiro ◽  
Ana Margarida Moreira ◽  
Maria Sofia Fernandes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Genetic Alterations ◽  
Tumour Suppressor Gene ◽  
Diffuse Gastric Cancer ◽  
Loss Of Function ◽  
Lobular Breast Cancer ◽  
Cancer Syndrome ◽  
Risk Of Cancer ◽  
E Cadherin

CDH1 encodes E-cadherin, a key protein in adherens junctions. Given that E-cadherin is involved in major cellular processes such as embryogenesis and maintenance of tissue architecture, it is no surprise that deleterious effects arise from its loss of function. E-cadherin is recognised as a tumour suppressor gene, and it is well established that CDH1 genetic alterations cause diffuse gastric cancer and lobular breast cancer—the foremost manifestations of the hereditary diffuse gastric cancer syndrome. However, in the last decade, evidence has emerged demonstrating that CDH1 mutations can be associated with lobular breast cancer and/or several congenital abnormalities, without any personal or family history of diffuse gastric cancer. To date, no genotype–phenotype correlations have been observed. Remarkably, there are reports of mutations affecting the same nucleotide but inducing distinct clinical outcomes. In this review, we bring together a comprehensive analysis of CDH1-associated disorders and germline alterations found in each trait, providing important insights into the biological mechanisms underlying E-cadherin’s pleiotropic effects. Ultimately, this knowledge will impact genetic counselling and will be relevant to the assessment of risk of cancer development or congenital malformations in CDH1 mutation carriers.

scholarly journals Allosteric AKT Inhibitors Target Synthetic Lethal Vulnerabilities in E-Cadherin-Deficient Cells

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1359 ◽  
Author(s):  
Nicola Bougen-Zhukov ◽  
Yasmin Nouri ◽  
Tanis Godwin ◽  
Megan Taylor ◽  
Christopher Hakkaart ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Bioinformatic Analysis ◽  
Normal Breast ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
Gastric Cancer Cells ◽  
Gene Encoding ◽  
Enhanced Sensitivity ◽  
Mcf10a Cells ◽  
E Cadherin

The CDH1 gene, encoding the cell adhesion protein E-cadherin, is one of the most frequently mutated genes in gastric cancer and inactivating germline CDH1 mutations are responsible for hereditary diffuse gastric cancer syndrome (HDGC). Using cell viability assays, we identified that breast (MCF10A) and gastric (NCI-N87) cells lacking CDH1 expression are more sensitive to allosteric AKT inhibitors than their CDH1-expressing isogenic counterparts. Apoptosis priming and total apoptosis assays in the isogenic MCF10A cells confirmed the enhanced sensitivity of E-cadherin-null cells to the AKT inhibitors. In addition, two of these inhibitors, ARQ-092 and MK2206, preferentially targeted mouse-derived gastric Cdh1−/− organoids for growth arrest. AKT protein expression and activation (as measured by phosphorylation of serine 473) were differentially regulated in E-cadherin-null MCF10A and NCI-N87 cells, with downregulation in the normal breast cells, but upregulation in the gastric cancer cells. Bioinformatic analysis of the TCGA STAD dataset revealed that AKT3, but not AKT1 or AKT2, is upregulated in the majority of E-cadherin-deficient gastric cancers. In conclusion, allosteric AKT inhibitors represent a promising class of drugs for chemoprevention and chemotherapy of cancers with E-cadherin loss.

scholarly journals Family’s History Based on the CDH1 Germline Variant (c.360delG) and a Suspected Hereditary Gastric Cancer Form

2020 ◽  
Vol 21 (14) ◽  
pp. 4904
Author(s):  
Laura Caggiari ◽  
Mara Fornasarig ◽  
Mariangela De Zorzi ◽  
Renato Cannizzaro ◽  
Agostino Steffan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Susceptibility ◽  
Stop Codon ◽  
Case Reports ◽  
Premature Stop Codon ◽  
Diffuse Gastric Cancer ◽  
Cancer Syndrome ◽  
The Family ◽  
Hereditary Gastric Cancer ◽  
E Cadherin

Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by germline pathogenic variant in CDH1, the gene encoding E-cadherin. The germline loss-of-function variants are the only proven cause of the cancer syndrome HDGC, occurring in approximately 10–18% of cases and representing a helpful tool in genetic counseling. The current case reports the family history based on a CDH1 gene variant, c.360delG, p.His121Thr in a suspected family for hereditary gastric cancer form. This frameshift deletion generates a premature stop codon at the amino acid 214, which leads to a truncated E-cadherin protein detecting it as a deleterious variant. The present study expands the mutational spectra of the family with the CDH1 variant. Our results highlight the clinical impact of the reported CDH1 variant running in gastric cancer families.

Prognostic Analysis of E-Cadherin Gene Promoter Hypermethylation in Patients with Surgically Resected, Node-Positive, Diffuse Gastric Cancer

2004 ◽  
Vol 10 (8) ◽  
pp. 2784-2789 ◽  
Author(s):  
Francesco Graziano ◽  
Federica Arduini ◽  
Annamaria Ruzzo ◽  
Italo Bearzi ◽  
Bostjan Humar ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Gene Promoter ◽  
Promoter Hypermethylation ◽  
Diffuse Gastric Cancer ◽  
Node Positive ◽  
Prognostic Analysis ◽  
Resected Node ◽  
E Cadherin

scholarly journals Germline mutations of the E-cadherin gene in families with inherited invasive lobular breast carcinoma but no diffuse gastric cancer

Cancer ◽  
2011 ◽  
Vol 117 (14) ◽  
pp. 3112-3117 ◽  
Author(s):  
Ze Ming Xie ◽  
Lai Sheng Li ◽  
Claire Laquet ◽  
Frédérique Penault-Llorca ◽  
Nancy Uhrhammer ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Breast Carcinoma ◽  
Germline Mutations ◽  
Diffuse Gastric Cancer ◽  
Lobular Breast Carcinoma ◽  
E Cadherin

scholarly journals Early-onset diffuse gastric cancer associated with a de novo large genomic deletion of CDH1 gene

2013 ◽  
Vol 17 (4) ◽  
pp. 745-749 ◽  
Author(s):  
Shinya Sugimoto ◽  
Hidetaka Yamada ◽  
Masazumi Takahashi ◽  
Yuichi Morohoshi ◽  
Naotaka Yamaguchi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Early Onset ◽  
De Novo ◽  
Diffuse Gastric Cancer ◽  
Cdh1 Gene ◽  
Genomic Deletion ◽  
Large Genomic Deletion

Searching for CDH1 gene mutations in early-onset diffuse gastric cancer in Chinese patients.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 23-23
Author(s):  
Xu Yanjun ◽  
Cao Wenming ◽  
Xu Qi ◽  
Guo Jianmin ◽  
Wang Xinbao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Overall Survival ◽  
Lymph Node ◽  
Gene Mutations ◽  
Germline Mutations ◽  
Chinese Patients ◽  
Diffuse Gastric Cancer ◽  
Cdh1 Gene ◽  
Node Metastasis ◽  
Cdh1 Mutation

23 Background: CDH1 germline mutations are found to be associated with the development of hereditary diffuse gastric cancer (HDGC) and the early-onset diffuse gastric cancer (EODGC). But the impact of CDH1 gene mutations and large deletions on HDGC and EODGC has not been fully determined in Asians. Although the incidence of gastric cancer is relatively high in China, the detection rate of CDH1 germline mutations in Chinese patients with EODGC is rare compared to that in European patients. Methods: We investigated the mutation status of the CDH1 gene in 57 Chinese EODGC patients younger than 40 years old who met the clinical criteria for HDGC. Polymerase chain reaction-direct sequencing was performed, and multiplex ligation-dependent probe amplification (MLPA) was used to evaluate the patients with negative sequencing results. Associations between mutation, clinicopathologic, and overall survival data were analyzed by SPSS 19. Results: The germline mutations of CDH1gene were identified in 51 (89.5%) of the 57 EODGC patients. The nonsense mutation in exon 13 (c.2200T>C, p.Ala692*) occurred in fourty-six EODGC patients. The missense mutations were detected in twenty patients (Eighteen in exon 5: c.778G>C, p.Glu218Asp; Two in exon 12: c.2012C>G, p.Leu630Val). No deletion or duplication in any patient. Most of the patients carrying the CDH1 mutation in exon 13 had lymph node metastasis when compared with patients lacking CDH1 mutation (87.2% vs 60.0%) ( P < 0.05 ). EODGC patients, lacking germline CDH1 alterations, showed a longer median overall survival (mOS) than patients carrying CDH1 mutation in exon 13 ( P < 0.05 ). Moreover, the presence of CDH1 mutation in exon 13 was associated with the incidence of neural invasion ( P < 0.05 ). Conclusions: This study reveals novel CDH1 mutations in Chinese EODGC patients which had been poorly investigated. The presence of CDH1 mutation in EODGC patients may result in lymph node metastasis and poor prognosis. More research is needed to determine additional genetic targets that trigger EODGC.

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