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PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1/2.
- Source :
-
Cell death & disease [Cell Death Dis] 2020 Jul 06; Vol. 11 (7), pp. 507. Date of Electronic Publication: 2020 Jul 06. - Publication Year :
- 2020
-
Abstract
- Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), an essential enzyme involved in de novo purine biosynthesis, is connected with formation of various tumors. However, the specific biological roles and related mechanisms of PAICS in gastric cancer (GC) remain unclear. In the present study, we identified for the first time that PAICS was significantly upregulated in GC and high expression of PAICS was correlated with poor prognosis of patients with GC. In addition, knockdown of PAICS significantly induced cell apoptosis, and inhibited GC cell growth both in vitro and in vivo. Mechanistic studies first found that PAICS was engaged in DNA damage response, and knockdown of PAICS in GC cell lines induced DNA damage and impaired DNA damage repair efficiency. Further explorations revealed that PAICS interacted with histone deacetylase HDAC1 and HDAC2, and PAICS deficiency decreased the expression of DAD51 and inhibited its recruitment to DNA damage sites by impairing HDAC1/2 deacetylase activity, eventually preventing DNA damage repair. Consistently, PAICS deficiency enhanced the sensitivity of GC cells to DNA damage agent, cisplatin (CDDP), both in vitro and in vivo. Altogether, our findings demonstrate that PAICS plays an oncogenic role in GC, which act as a novel diagnosis and prognostic biomarker for patients with GC.
- Subjects :
- Animals
Apoptosis genetics
Carcinogenesis metabolism
Cell Line, Tumor
Cell Proliferation genetics
Cisplatin pharmacology
DNA Repair
Gene Expression Regulation, Enzymologic
Gene Knockdown Techniques
HEK293 Cells
Humans
Male
Mice, Inbred BALB C
Mice, Nude
Models, Biological
Peptide Synthases deficiency
Prognosis
Protein Binding
Up-Regulation genetics
Carcinogenesis pathology
DNA Damage
Histone Deacetylase 1 metabolism
Histone Deacetylase 2 metabolism
Peptide Synthases metabolism
Stomach Neoplasms enzymology
Stomach Neoplasms pathology
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 11
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 32632107
- Full Text :
- https://doi.org/10.1038/s41419-020-2708-5