Josephin domain containing 2 (JOSD2) promotes lung cancer by inhibiting LKB1 (Liver kinase B1) activity.
Josephin domain containing 2 (JOSD2) promotes lung cancer by inhibiting LKB1 (Liver kinase B1) activity.
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Josephin domain containing 2（JOSD 2）通过抑制LKB 1（肝激酶B1）活性促进肺癌。
DOI：
10.1038/s41392-023-01706-y
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发表时间：
2024-01-05
影响因子：
39.3
通讯作者：
Yang, Bo
中科院分区：
文献类型：
--
作者：
Yuan, Tao;Zeng, Chenming;Liu, Jiawei;Zhao, Chenxi;Ge, Fujing;Li, Yuekang;Qian, Meijia;Du, Jiamin;Wang, Weihua;Li, Yonghao;Liu, Yue;Dai, Xiaoyang;Zhou, Jianya;Chen, Xueqin;Ma, Shenglin;Zhu, Hong;He, Qiaojun;Yang, Bo
非小细胞肺癌(NSCLC)是全球癌症相关死亡的主要原因之一。尽管激酶靶向疗法在非小细胞肺癌治疗中的重要性和有效性，但这些药物只适用于并有益于只有30%的非小细胞肺癌患者。因此，迫切需要新的战略来解决非小细胞肺癌问题。去泛素酶(DUBS)是一组具有明确催化位点的多种酶，在癌症中经常过度激活，与肿瘤的发生有关，被认为是有希望的治疗靶点。然而，DUBS促进非小细胞肺癌的机制仍然知之甚少。通过使用癌症基因组图谱(TCGA)数据库对97个DUBS对NSCLC生存可能性的贡献进行全球分析，我们发现约瑟芬结构域包含蛋白2(JOSD2)的高表达预示着患者的不良预后。在体内，JOSD2的缺失显著阻碍了细胞/患者来源的异种移植中NSCLC的生长。从机械上讲，我们发现JOSD2通过移除K6连接的多泛素化来限制LKB1的激酶活性，LKB1是一种重要的肿瘤抑制因子，在非小细胞肺癌中通常是失活的，这是一种对维持LKB1-Strad-MO25复合体的完整性至关重要的动作。值得注意的是，我们确定了第一个JOSD2的小分子抑制剂，并观察到它的药理抑制作用在体外/体内显著抑制了NSCLC的增殖。我们的发现强调了JOSD2在阻碍LKB1活性方面的重要作用，强调了靶向JOSD2在非小细胞肺癌中的治疗潜力，特别是在那些LKB1失活的患者中，并提出了其抑制剂作为一种有前景的非小细胞肺癌治疗策略。
Non-small cell lung cancer (NSCLC) ranks as one of the leading causes of cancer-related deaths worldwide. Despite the prominence and effectiveness of kinase-target therapies in NSCLC treatment, these drugs are suitable for and beneficial to a mere ~30% of NSCLC patients. Consequently, the need for novel strategies addressing NSCLC remains pressing. Deubiquitinases (DUBs), a group of diverse enzymes with well-defined catalytic sites that are frequently overactivated in cancers and associated with tumorigenesis and regarded as promising therapeutic targets. Nevertheless, the mechanisms by which DUBs promote NSCLC remain poorly understood. Through a global analysis of the 97 DUBs’ contribution to NSCLC survival possibilities using The Cancer Genome Atlas (TCGA) database, we found that high expression of Josephin Domain-containing protein 2 (JOSD2) predicted the poor prognosis of patients. Depletion of JOSD2 significantly impeded NSCLC growth in both cell/patient-derived xenografts in vivo. Mechanically, we found that JOSD2 restricts the kinase activity of LKB1, an important tumor suppressor generally inactivated in NSCLC, by removing K6-linked polyubiquitination, an action vital for maintaining the integrity of the LKB1-STRAD-MO25 complex. Notably, we identified the first small-molecule inhibitor of JOSD2, and observed that its pharmacological inhibition significantly arrested NSCLC proliferation in vitro/in vivo. Our findings highlight the vital role of JOSD2 in hindering LKB1 activity, underscoring the therapeutic potential of targeting JOSD2 in NSCLC, especially in those with inactivated LKB1, and presenting its inhibitors as a promising strategy for NSCLC treatment.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
50.3
作者：
Carretero J;Shimamura T;Rikova K;Jackson AL;Wilkerson MD;Borgman CL;Buttarazzi MS;Sanofsky BA;McNamara KL;Brandstetter KA;Walton ZE;Gu TL;Silva JC;Crosby K;Shapiro GI;Maira SM;Ji H;Castrillon DH;Kim CF;García-Echeverría C;Bardeesy N;Sharpless NE;Hayes ND;Kim WY;Engelman JA;Wong KK
通讯作者：
Wong KK
DOI：
10.1038/nrd.2017.152
发表时间：
2018-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Harrigan JA;Jacq X;Martin NM;Jackson SP
通讯作者：
Jackson SP
影响因子：
8
作者：
Carretero, J;Medina, PP;Sanchez-Cespedes, M
通讯作者：
Sanchez-Cespedes, M
影响因子：
3.9
作者：
Huang, Yao;Zeng, Jianxing;Zeng, Jinhua
通讯作者：
Zeng, Jinhua