Journal
GASTRIC CANCER
Volume 24, Issue 1, Pages 60-71Publisher
SPRINGER
DOI: 10.1007/s10120-020-01094-0
Keywords
ARID1A; EZH2; Synthetic lethality; Gastric cancer
Categories
Funding
- JSPS KAKENHI [18K08652, 19K09099]
- Grants-in-Aid for Scientific Research [18K08652, 19K09099] Funding Source: KAKEN
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EZH2 inhibitors show selective sensitivity against ARID1A-deficient GC cells, potentially affecting cell survival and proliferation by modulating the PI3K/AKT signaling pathway. This suggests the potential efficacy of targeted therapy using EZH2 inhibitors in ARID1A-deficient GC.
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. 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. 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. 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.
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