PAICS contributes to gastric carcinogenesis and participates in DNA damage response by interacting with histone deacetylase 1/2

Nan Huang,Yue Zhang,Fenyong Sun,Ni Zhen,Shuping Long,Zhixuan Bian,Yan Chen,Xue Li,Guohui Li,Liang Deng,Chang Xu

doi:10.1038/s41419-020-2708-5

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.

Highlights

Gastric cancer (GC) is the fifth most common malignancy and third leading cause of cancer-related death worldwide with the annual death rate in China accounting for more than 40% of the world[1]
As a key regulatory enzyme involved in the de novo purine biosynthesis pathway, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) plays an important role in maintaining normal metabolism[5,6]
Our results showed that both homologous recombination repair (HR) and NHEJ efficiency were inhibited with PAICS knockdown

Summary

Introduction

Gastric cancer (GC) is the fifth most common malignancy and third leading cause of cancer-related death worldwide with the annual death rate in China accounting for more than 40% of the world[1]. The prognosis of most patients with advanced GC remains poor mostly because of chemotherapy resistance, which is Phosphoribosylaminoimidazole carboxylase, phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is a putative bifunctional enzyme involved in the de novo purine biosynthesis pathway with both 5aminoimidazole ribonucleotide carboxylase and 4-(Nsuccinylcarbox-amide)-5-aminoimidazole ribonucleotide synthetase activities[5]. Previous study has demonstrated that cancer cells rely on the PAICS-dependent metabolic pathway for adenosine monophosphate and guanosine monophosphate synthesis, and inactivation of the de novo pathway inhibits cancer cell proliferation both in vitro and Official journal of the Cell Death Differentiation Association. A study of the oncogenic mechanism of PAICS has revealed that PAICS can induce epithelialmesenchymal transition in bladder cancer by positively regulating SNAI1 and reducing E-cadherin expression[9]. The specific biological roles and related mechanisms of PAICS in GC remain unclear

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Results

Conclusion