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Selective sensitivity of EZH2 inhibitors based on synthetic lethality in ARID1A-deficient gastric cancer.
- Source :
-
Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association [Gastric Cancer] 2021 Jan; Vol. 24 (1), pp. 60-71. Date of Electronic Publication: 2020 Jun 06. - Publication Year :
- 2021
-
Abstract
- Background: AT-rich interactive domain 1A (ARID1A) is a tumor suppressor gene that is frequently mutated in gastric cancer (GC). Although ARID1A mutations are not a druggable target for conventional treatments, novel therapeutic strategies based on a synthetic lethal approach are effective for ARID1A-deficient cancers. The histone methyltransferase EZH2 acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer, although its role in GC remains unknown.<br />Methods: The selective sensitivity of the EZH2 inhibitors for ARID1A-deficient GC cells was evaluated using cell viability and colony formation assays. The expression of PI3K/AKT signaling genes were investigated using TCGA's cBioPortal database to determine whether the homeostasis between ARID1A and EZH2 is related to cell proliferation and survival via the PI3K/AKT signaling pathway. We also evaluated the phosphorylation of PI3K/AKT signaling proteins in ARID1A knock downed ARID1A-WT GC cells.<br />Results: EZH2 inhibitors decreased the viability of ARID1A-deficient cells in a dose-dependent manner and demonstrated the selective sensitivity to ARID1A-deficient cells in vitro experiment system. Bioinformatics approach revealed that the PI3K/AKT signaling was tended to be activated in ARID1A-deficient GC enhancing cell viability and, furthermore, down-regulation of EZH2 in ARID1A-deficient GC was related to normalization of PI3K/AKT signaling pathway. The cell experiment revealed that phosphorylated AKT was upregulated in ARID1A-deficent GC cells.<br />Conclusions: The present findings provide a rationale for the selective sensitivity of EZH2 inhibitors against ARID1A-deficient GC and suggest the potential efficacy of targeted therapy using EZH2 inhibitors in this patient population.
- Subjects :
- Cell Line, Tumor
Cell Proliferation drug effects
Cell Survival drug effects
Drug Screening Assays, Antitumor
Gene Knockdown Techniques
Humans
Oncogene Protein v-akt metabolism
Phosphatidylinositol 3-Kinases metabolism
Phosphorylation drug effects
Signal Transduction drug effects
Stomach Neoplasms genetics
Up-Regulation drug effects
Antineoplastic Agents pharmacology
DNA-Binding Proteins deficiency
Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors
Enzyme Inhibitors pharmacology
Stomach Neoplasms drug therapy
Synthetic Lethal Mutations drug effects
Transcription Factors deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1436-3305
- Volume :
- 24
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association
- Publication Type :
- Academic Journal
- Accession number :
- 32506298
- Full Text :
- https://doi.org/10.1007/s10120-020-01094-0