Abstract
Poly (ADP-ribose) glycohydrolase (PARG) is the main enzyme responsible for catabolism of poly (ADP-ribose) (PAR), synthesized by PARP. PARG dysfunction sensitizes certain cancer cells to alkylating agents and cisplatin by perturbing the DNA damage response. The gene mutations that sensitize cancer cells to PARG dysfunction-induced death remain to be identified. Here, we performed a comprehensive analysis of synthetic lethal genes using inducible PARG knockdown cells and identified dual specificity phosphatase 22 (DUSP22) as a novel synthetic lethal gene related to PARG dysfunction. DUSP22 is considered a tumor suppressor and its mutation has been frequently reported in lung, colon, and other tumors. In the absence of DNA damage, dual depletion of PARG and DUSP22 in HeLa and lung cancer A549 cells reduced survival compared with single-knockdown counterparts. Dual depletion of PARG and DUSP22 increased the apoptotic sub-G1 fraction and upregulated PUMA in lung cancer A549, PC14, and SBC5 cells, and inhibited the PI3K/AKT/mTOR pathway in A549 cells, suggesting that dual depletion of PARG and DUSP22 induced apoptosis by upregulating PUMA and suppressing the PI3K/AKT/mTOR pathway. Consistently, the growth of tumors derived from double knockdown A549 cells was slower compared with those derived from control siRNA-transfected cells. Taken together, these results indicate that DUSP22 deficiency exerts a synthetic lethal effect when combined with PARG dysfunction, suggesting that DUSP22 dysfunction could be a useful biomarker for cancer therapy using PARG inhibitors. SIGNIFICANCE: This study identified DUSP22 as a novel synthetic lethal gene under the condition of PARG dysfunction and elucidated the mechanism of synthetic lethality in lung cancer cells.
Highlights
(ADP-ribosylation) is a posttranslational modification by which some PARP family proteins catalyze the transfer ofNote: Supplementary data for this article are available at Cancer Research Online.Y
Because the frequency of dual specificity phosphatase 22 (DUSP22) mutation is higher in lung cancer than in other types of tumors (Fig. 1C), we examined whether DUSP22 and Poly (ADP-ribose) glycohydrolase (PARG) dysfunction induced synthetic lethality in the lung cancer cell lines A549, PC14, and SBC5
A PARP inhibitor, was approved for the treatment of ovarian cancer harboring BRCA1/2 mutations, and this novel type of anticancer agent is effective as monotherapy against BRCA1/2-mutated cancers [5, 35]
Summary
(ADP-ribosylation) is a posttranslational modification by which some PARP family proteins catalyze the transfer ofNote: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).Y. ADP-ribose to target proteins in a nicotinamide adenine dinucleotide (NADþ)-dependent manner [1, 2]. This reaction is involved in various biological processes, including cell death, chromatin regulation, and DNA repair of single-strand breaks (SSB) and double-strand breaks PARP inhibitors were recently developed as a novel anticancer agent based on the concept of synthetic lethality [4, 5]. The development of novel anticancer agents based on the concept of synthetic lethality is a valuable cancer chemotherapy strategy because these drugs show increased tumor selectivity with reduced adverse effects on normal cells [4]
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