HMGB3 promotes PARP inhibitor resistance through interacting with PARP1 in ovarian cancer.
HMGB3 promotes PARP inhibitor resistance through interacting with PARP1 in ovarian cancer.
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HMGB3 通过与卵巢癌中的 PARP1 相互作用促进 PARP 抑制剂耐药性
DOI：
10.1038/s41419-022-04670-7
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发表时间：
2022-03-24
影响因子：
9
通讯作者：
Kong B
中科院分区：
文献类型：
--
作者：
Ma H;Qi G;Han F;Lu W;Peng J;Li R;Yan S;Yuan C;Kong B
聚（adp -核糖）聚合酶（PARP）抑制剂（PARPi）耐药仍然是卵巢癌治疗的一个挑战。高迁移率群盒3 （HMGB3）在多种癌症的耐药发展中起着重要作用。然而，HMGB3在PARPi抗性中的作用尚不清楚。在本研究中，我们明确了HMGB3在高级别浆液性卵巢癌（HGSOC）组织中异常过表达，高水平的HMGB3表明HGSOC的总生存期较短，耐药。HMGB3过表达增加了卵巢癌对PARPi的不敏感性，而HMGB3敲低则降低了PARPi的耐药性。在机制上，PARP1被确定为HMGB3的一个新的相互作用伙伴，可以用奥拉帕尼阻断，并在DNA损伤条件下增强。我们进一步发现，HMGB3的缺失诱导PARP1在DNA损伤处被捕获，并抑制PARP1的PARylation活性，导致DNA损伤反应增加和细胞凋亡。在异种移植小鼠模型中也证实了HMGB3的parpi抗性作用。综上所述，HMGB3通过与PARP1相互作用促进PARPi耐药，靶向抑制HMGB3可能在卵巢癌治疗中克服PARPi耐药。
Poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) resistance remains a therapeutic challenge in ovarian cancer. High-mobility group box 3 (HMGB3) plays significant roles in the development of drug resistance of many cancers. However, the function of HMGB3 in PARPi resistance is poorly understood. In the current study, we clarified that HMGB3 was aberrantly overexpressed in high-grade serous ovarian carcinoma (HGSOC) tissues, and high HMGB3 levels indicated shorter overall survival and drug resistance in HGSOC. The overexpression of HMGB3 increased the insensitivity of ovarian cancer to PARPi, whereas HMGB3 knockdown reduced PARPi resistance. Mechanistically, PARP1 was identified as a novel interaction partner of HMGB3, which could be blocked using olaparib and was enhanced upon DNA damage conditions. We further showed that loss of HMGB3 induced PARP1 trapping at DNA lesions and inhibited the PARylation activity of PARP1, resulting in an increased DNA damage response and cell apoptosis. The PARPi-resistant role of HMGB3 was also verified in a xenograft mouse model. In conclusion, HMGB3 promoted PARPi resistance via interacting with PARP1, and the targeted inhibition of HMGB3 might overcome PARPi resistance in ovarian cancer therapy.
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影响因子：
51.1
作者：
Pujade-Lauraine, Eric;Ledermann, Jonathan A.;Pautier, Patricia
通讯作者：
Pautier, Patricia
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
11.2
作者：
Mukherjee, Anirban;Van Huynh;Vasquez, Karen M.
通讯作者：
Vasquez, Karen M.
影响因子：
13.6
作者：
Lombard DB;Kohler WJ;Guo AH;Gendron C;Han M;Ding W;Lyu Y;Ching TT;Wang FY;Chakraborty TS;Nikolovska-Coleska Z;Duan Y;Girke T;Hsu AL;Pletcher SD;Miller RA
通讯作者：
Miller RA
针对宫颈癌放射抗性的 HMGB3/hTERT 轴。
DOI：
10.1186/s13046-020-01737-1
发表时间：
2020-11-13
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Li Z;Zhang Y;Sui S;Hua Y;Zhao A;Tian X;Wang R;Guo W;Yu W;Zou K;Deng W;He L;Zou L
通讯作者：
Zou L