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Dysfunction of Poly(ADP-Ribose) Glycohydrolase Induces a Synthetic Lethal Effect in Dual Specificity Phosphatase 22-Deficient Lung Cancer Cells

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Dysfunction of Poly(ADP-Ribose) Glycohydrolase Induces a Synthetic Lethal Effect in Dual Specificity Phosphatase 22-Deficient Lung Cancer Cells Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-1037 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Title Dysfunction of poly(ADP-ribose) glycohydrolase induces a synthetic lethal effect in dual specificity phosphatase 22-deficient lung cancer cells. Authors and affiliations Yuka Sasaki1,2*, Hiroaki Fujimori1,2*, Miyuki Hozumi2,3, Takae Onodera1,2, Tadashige Nozaki1,4, Yasufumi Murakami3, Kazuto Ashizawa5, Kengo Inoue6, Fumiaki Koizumi7, Mitsuko Masutani1,2 1Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan 2Division of Chemotherapy and Clinical Research, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan 3Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, 6-3-1 Niijuku, Katsushika-ku, Tokyo, 125-8585, Japan 4Department of Pharmacology, Faculty of Dentistry, Osaka Dental University, 8-1, Kuzuhahanazono-cho, Hirakata, Osaka, 573-1121, Japan 5Department of Clinical Oncology, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan 6Pharma Valley Center, 1007 Shimonagakubo, Nagaizumi-cho, Shunto-gun, Shizuoka, 411-8777, Japan 7Department of Laboratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, 3-18-22, Honkomagome, Bunkyo-ku, Tokyo, 113-8677, Japan *Equally contributed. Running title Dysfunction of PARG and DUSP22 induces synthetic lethality Keywords PARG, poly(ADP-ribose), synthetic lethality, DUSP22, cancer therapy A conflict of interest disclosure statement We have no financial relationships to disclose. 1 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-1037 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Financial supports This research is partially supported by The Practical Research for Innovative Cancer Control from Japan Agency for Medical Research and Development, AMED (15Ack0106021, 17ck0106286), and Grant-in-Aid for Scientific Research (KibanB 22300343, H23-Jitsuyoka(Gan)-004) to M.M. Corresponding author Mitsuko Masutani Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan Phone and Fax: +81-95-819-8502 E-mail address: [email protected] 227 words of abstract 6124 words of text 1 table and 6 figures 2 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-1037 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 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 to 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. Statement of 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. 3 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-1037 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Poly(ADP-ribosylation) is a post-translational modification by which some PARP family proteins catalyze the transfer of ADP-ribose to target proteins in a nicotinamide adenine dinucleotide (NAD+)-dependent manner (1,2). This reaction is involved in various biological processes, including cell death, chromatin regulation, and DNA repair of single strand breaks (SSBs) and double strand breaks (DSBs) (1,3). PARP inhibitors were recently developed as a novel anticancer agent based on the concept of synthetic lethality (4,5). PARP inhibitors selectively induce cell death in homologous recombination repair (HRR)-deficient cancers such as those associated with mutations in BRCA1/2 (6,7), RAD51 (8), and PTEN (9). 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). Poly(ADP-ribose) (PAR) synthesized by PARP is rapidly degraded to ADP-ribose by poly(ADP-ribose) glycohydrolase (PARG) (10) and ADP-ribosyl hydrolase (ARH3) (11). PARG is the main enzyme catabolizing PAR to ADP-ribose through its endo- and exo-glycohydrolase activities (12). As previously reported, PARG is required for the efficient repair of DSBs and SSBs (13). PARG deficiency induces PAR accumulation and a delay of DNA repair (14,15). And, PAR accumulation induces cell death (parthanatos) accompanied by the translocation of apoptosis inducing factor from mitochondria to nuclei, leading to fragmentation of large-sized DNA in neuronal cells and cancer cells such as HeLa cells (16,17). As previously reported, certain human cancer cell lines with PARG knockdown synergistically show higher sensitivity to alkylating agents (14,18) and cisplatin treatment (18). PARG hypomorphic mouse ES cells with residual 10% PARG activity did not exhibit growth defect but showed higher sensitivity to alkylating agents, cisplatin, photon and particle beam irradiation compared to wild-type ES cells (14,19,20). In addition, BRCA2 (21) and Bruton’s tyrosine kinase (BTK) (22) defects increase PARG inhibition-induced cytotoxicity (21-23). These findings led us to hypothesize that PARG could serve as a novel therapeutic target for anticancer agents in both monotherapy and combination therapy with radiotherapy or other DNA targeting chemotherapeutic agents for particular types of cancers. Recently, PARG inhibitors such as phenolic hydrazide hydrazones (24), 4 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-1037 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. rhodanine-based PARG inhibitors (RBPIs) (25), xanthene compounds (26), ADP-HPD (27), and PDD00017273 (28), which has an IC50 in the sub-microM range, have been developed. However, specific and potent PARG inhibitors for clinical applications remain to be developed. Here, we screened genes whose deficiency enhances sensitivity in a synthetic lethal manner to develop a novel anticancer agent targeting PARG. We identified dual specificity phosphatase 22 (DUSP22) as such a novel gene. Synthetic lethality induced by PARG and DUSP22 dysfunction in lung cancer cells led to TP63-dependent apoptosis by upregulating p53 upregulated modulator of apoptosis (PUMA). Double knockdown of PARG and DUSP22 inhibited tumor growth in a mouse xenograft model. These results indicated that alterations in DUSP22 expression levels may serve as a predictive biomarker for PARG inhibitors. 5 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on May 29, 2019; DOI: 10.1158/0008-5472.CAN-18-1037 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Materials and methods Cell culture and reagents The TRHmPARG#8 cell line is a tetracycline-inducible PARG knockdown strain derived from the human T-REx HeLa cell line described previously (29). TRHmPARG#8 and PC14 were cultured in Minimum Essential Medium and Dulbecco’s modified Eagle’s medium (Thermo Fisher Scientific), respectively. A549 and SBC5 cells were grown in RPMI1640 (Thermo Fisher Scientific). Media were supplemented with 10% fetal
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