Overexpression of tripartite motif-containing 47 (TRIM47) confers sensitivity to PARP inhibition via ubiquitylation of BRCA1 in triple negative breast cancer cells.
Overexpression of tripartite motif-containing 47 (TRIM47) confers sensitivity to PARP inhibition via ubiquitylation of BRCA1 in triple negative breast cancer cells.
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DOI：
10.1038/s41389-023-00453-7
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发表时间：
2023-03-11
期刊：
影响因子：
6.2
通讯作者：
Li, Heping
中科院分区：
文献类型：
--
作者：
Liu, Fengen;Xie, Binhui;Ye, Rong;Xie, Yuankang;Zhong, Baiyin;Zhu, Jinrong;Tang, Yao;Lin, Zelong;Tang, Huiru;Wu, Ziqing;Li, Heping
三阴性乳腺癌（TNBC）经常通过同源重组（HR）在DNA双链断裂修复中存在缺陷，如BRCA 1功能障碍。然而，不到15%的TNBC患者被发现携带BRCA 1突变，这表明在TNBC中存在其他调节BRCA 1缺陷的机制。在目前的研究中，我们发现TRIM 47的过表达与三阴性乳腺癌的进展和预后不良相关。此外，我们证明TRIM 47直接与BRCA 1相互作用，并诱导泛素连接酶介导的BRCA 1蛋白酶体转换，随后导致TNBC中BRCA 1蛋白水平的降低。BRCA 1下游基因p53、p27、p21的表达在TRIM 47过表达的细胞系中明显降低，而在TRIM 47缺失的细胞中则明显升高。在功能上，我们发现TRIM 47在TNBC细胞中的过表达赋予了对奥拉帕尼（一种聚-（ADP-核糖）-聚合酶（PARP）的抑制剂）的灵敏度，但TRIM 47抑制显著赋予TNBC细胞在体外和体内对奥拉帕尼的抗性。此外，我们发现BRCA 1的过表达显著增加了TRIM 47过表达诱导的PARP抑制敏感性中的奥拉帕尼抗性。综上所述，我们的研究结果揭示了TNBC中BRCA 1缺陷的新机制，靶向TRIM 47/BRCA 1轴可能是一个有前途的预后因素和TNBC有价值的治疗靶点。
Triple-negative breast cancers (TNBC) frequently harbor defects in DNA double-strand break repair through homologous recombination (HR), such as BRCA1 dysfunction. However, less than 15% of TNBC patients were found to carry BRCA1 mutation, indicating that there are other mechanisms regulating BRCA1-deficient in TNBC. In the current study, we shown that overexpression of TRIM47 correlates with progression and poor prognosis in triple-negative breast cancer. Moreover, we demonstrated that TRIM47 directly interacts with BRCA1 and induces ubiquitin-ligase-mediated proteasome turnover of BRCA1, subsequently leads to a decrease of BRCA1 protein levels in TNBC. Moreover, the downstream gene expression of BRCA1, such as p53, p27, p21 was significantly reduced in the overexpression of TRIM47 cell lines but increased in TRIM47-deleted cells. Functionally, we found that overexpression of TRIM47 in TNBC cells confers an exquisite sensitivity to olaparib, an inhibitor of poly-(ADP-ribose)-polymerase (PARP), but TRIM47 inhibition significantly confers TNBC cells resistance to olaparib both in vitro and in vivo. Furthermore, we showed that overexpression of BRCA1 significant increase the olaparib resistance in TRIM47-overexpression-induced PARP inhibitions sensitivity. Taken together, our results uncover a novel mechanism for BRCA1-deficient in TNBC and targeting TRIM47/BRCA1 axis may be a promising prognostic factor and a valuable therapeutic target for TNBC.
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