Hepatitis B virus-associated hepatocellular carcinoma with Smc5/6 complex deficiency is susceptible to PARP inhibitors
Hepatitis B virus-associated hepatocellular carcinoma with Smc5/6 complex deficiency is susceptible to PARP inhibitors
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DOI：
10.1016/j.bbrc.2022.03.137
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发表时间：
2022-03-31
影响因子：
3.1
通讯作者：
Fujishiro, Mitsuhiro
中科院分区：
文献类型：
--
作者：
Funato, Kazuyoshi;Otsuka, Motoyuki;Fujishiro, Mitsuhiro
DNA修复过程代表了有吸引力的合成致死靶点，因为许多癌症表现出受损的DNA修复途径，这导致对特定修复蛋白的依赖。聚腺苷三磷酸聚合酶（PARP）-1抑制剂对同源重组缺陷的癌症非常有效的发现突出了这种方法的潜力。在B型肝炎病毒（HBV）感染中，HBV调节蛋白X（HBx）诱导染色体5/6（Smc 5/6）复合体结构维持的降解，该复合体在通过同源重组修复双链DNA断裂中起关键作用。在此，我们假设HBV相关肝细胞癌（HCC）中Smc 5/6复合物的缺陷通过同源重组的缺陷增加了对PARP抑制剂的敏感性。我们证实了受损的双链DNA断裂修复HBx表达肝癌细胞使用敏感的报告监测同源重组。用PARP抑制剂治疗对表达HBx的HCC细胞显著更有效，Smc 5/6的过表达阻止了这些作用。总的来说，我们的研究结果表明，HBV相关HCC中的同源重组缺陷导致对PARP抑制剂的敏感性增加。(C)2022爱思唯尔公司All rights reserved.
DNA repair processes represent attractive synthetic lethal targets because many cancers exhibit impaired DNA repair pathways, which leads to dependence on specific repair proteins. The finding that poly (ADPribose) polymerase (PARP)-1 inhibitors are highly effective against cancers with deficient homologous recombination highlights the potential of this approach. In hepatitis B viral (HBV) infection, degradation of the structural maintenance of the chromosome 5/6 ( Smc5/6) complex, which plays a key role in repairing double-stranded DNA breaks by homologous recombination, is induced by HBV regulatory protein X (HBx). Here, we hypothesized that a deficiency in the Smc5/6 complex in HBV-associated hepatocellular carcinoma (HCC) increases susceptibility to PARP inhibitors via a deficiency in homologous recombination. We confirmed impaired double-stranded DNA break repair in HBx-expressing HCC cells using a sensitive reporter to monitor homologous recombination. Treatment with a PARP inhibitor was significantly more effective against HBx-expressing HCC cells, and overexpression of Smc5/6 prevented these effects. Overall, our results suggest that homologous recombination deficiency in HBV-associated HCC leads to increased susceptibility to PARP inhibitors. (C) 2022 Elsevier Inc. All rights reserved.