Dysfunction of Poly (ADP-Ribose) Glycohydrolase Induces a Synthetic Lethal Effect in Dual Specificity Phosphatase 22-Deficient Lung Cancer Cells
Dysfunction of Poly (ADP-Ribose) Glycohydrolase Induces a Synthetic Lethal Effect in Dual Specificity Phosphatase 22-Deficient Lung Cancer Cells
复制标题
DOI：
10.1158/0008-5472.can-18-1037
复制
发表时间：
2019-08-01
期刊：
影响因子：
11.2
通讯作者：
Masutani, Mitsuko
中科院分区：
文献类型：
--
作者：
Sasaki, Yuka;Fujimori, Hiroaki;Masutani, Mitsuko
聚腺苷二磷酸核糖水解酶（Poly（ADP-ribose）glycohydrolase，PARG）是聚腺苷二磷酸核糖（Poly（ADP-ribose），PAR）合成的主要酶。PARG功能障碍通过扰乱DNA损伤反应使某些癌细胞对烷化剂和顺铂敏感。使癌细胞对PARG功能障碍诱导的死亡敏感的基因突变仍有待鉴定。在这里，我们进行了一个综合性的分析，使用诱导型PARG敲低细胞的合成致死基因，并确定了双特异性磷酸酶22（DUSP 22）作为一种新的合成致死基因与PARG功能障碍。DUSP 22被认为是一种肿瘤抑制因子，其突变在肺、结肠和其他肿瘤中经常被报道。在没有DNA损伤的情况下，与单敲低对应物相比，HeLa和肺癌A549细胞中PARG和DUSP 22的双重缺失降低了存活率。PARG和DUSP 22的双重缺失增加了肺癌A549、PC 14和SBC 5细胞中的凋亡亚G1分数并上调了PI 3 K/AKT/mTOR通路，并抑制了A549细胞中的PI 3 K/AKT/mTOR通路，这表明PARG和DUSP 22的双重缺失通过上调PI 3 K/AKT/mTOR通路并抑制PI 3 K/AKT/mTOR通路来诱导凋亡。一致地，与来自对照siRNA转染细胞的肿瘤相比，来自双敲低A549细胞的肿瘤生长较慢。综上所述，这些结果表明，DUSP 22缺陷在与PARG功能障碍组合时发挥合成致死作用，表明DUSP 22功能障碍可能是使用PARG抑制剂进行癌症治疗的有用生物标志物。重要性：本研究将DUSP 22鉴定为PARG功能障碍条件下的一个新的合成致死基因，并阐明了肺癌细胞合成致死的机制。
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.