MUS81 Inhibition Enhances the Anticancer Efficacy of Talazoparib by Impairing ATR/CHK1 Signaling Pathway in Gastric Cancer.
MUS81 Inhibition Enhances the Anticancer Efficacy of Talazoparib by Impairing ATR/CHK1 Signaling Pathway in Gastric Cancer.
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MUS81 抑制通过损害 ATR/CHK1 信号通路增强 Talazoparib 在胃癌中的抗癌功效
DOI：
10.3389/fonc.2022.844135
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发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
MUS81是与Eme1/Mms4形成异源二聚体的关键内切酶，也是重要的DNA损伤修复调控分子。我们前期研究提示MUS81过表达，其高表达与胃癌转移呈正相关。然而，靶向MUS81在胃癌中的治疗潜力有待进一步探索。因此，本研究通过对癌症基因组图谱（Cancer Genome Atlas， TCGA）数据的分析，发现MUS81是胃癌细胞周期分布和DNA损伤修复的关键调控因子。在体外和体内实验中，MUS81敲低显著增强了PARP抑制剂talazoparib的抗癌作用。从机制上看，MUS81抑制可抑制ATR/CHK1细胞周期信号通路的激活，促进talazoparib诱导DNA损伤的胃癌细胞继续有丝分裂。此外，添加含溴结构域蛋白4抑制剂AZD5153通过抑制胃癌细胞MUS81而增加了talazoparib的抗癌作用，当MUS81被敲除时，这种联合作用很大程度上被削弱。综上所述，这些数据表明MUS81调节G2M检查点关键信号通路ATR/CHK1的激活，靶向MUS81可增强talazoparib的抗肿瘤疗效。因此，AZD5153联合talazoparib可能是MUS81精通型胃癌患者的一种有前景的治疗策略。
MUS81 is a critical endonuclease involved in heterodimer formation with Eme1/Mms4 and an important DNA damage repair regulatory molecule. Our previous study suggested that MUS81 was overexpressed and its high expression was positively correlated with gastric cancer metastasis. However, the therapeutic potential of targeting MUS81 in gastric cancer requires further exploration. Therefore, in this study, the Cancer Genome Atlas (TCGA) data were analyzed and showed that MUS81 is a key regulator of cell cycle distribution and DNA damage repair in gastric cancer. In vitro and in vivo, MUS81 knockdown significantly enhanced the anticancer effect of the PARP inhibitor talazoparib. Mechanistically, MUS81 inhibition impaired the activation of the ATR/CHK1 cell cycle signaling pathway and promoted gastric cancer cells with talazoparib-induced DNA damage to continue mitosis. Moreover, addition of the bromodomain-containing protein 4 inhibitor AZD5153 increased the anticancer effect of talazoparib via MUS81 inhibition in gastric cancer cells, and this combination effect was largely impaired when MUS81 was knocked down. In conclusion, these data suggested that MUS81 regulated ATR/CHK1 activation, a key signaling pathway in the G2M checkpoint, and targeting MUS81 enhanced the antitumor efficacy of talazoparib. Therefore, AZD5153 combined with talazoparib may represent a promising therapeutic strategy for patients with MUS81 proficient gastric cancer.
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影响因子：
16
作者：
Liu S;Shiotani B;Lahiri M;Maréchal A;Tse A;Leung CC;Glover JN;Yang XH;Zou L
通讯作者：
Zou L
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影响因子：
4.7
作者：
Jia X;Guo T;Li Z;Zhang M;Feng Y;Dong B;Li Z;Hu Y;Li Z;Xing X;Jia S;Ji J
通讯作者：
Ji J
影响因子：
21.3
作者：
Jazayeri, A;Falck, J;Jackson, SP
通讯作者：
Jackson, SP
影响因子：
11.2
作者：
McCabe, Nuala;Turner, Nicholas C.;Ashworth, Alan
通讯作者：
Ashworth, Alan
影响因子：
7.7
作者：
Fang Z;Cao B;Liao JM;Deng J;Plummer KD;Liao P;Liu T;Zhang W;Zhang K;Li L;Margolin D;Zeng SX;Xiong J;Lu H
通讯作者：
Lu H