Deubiquitylase YOD1 regulates CDK1 stability and drives triple-negative breast cancer tumorigenesis.
Deubiquitylase YOD1 regulates CDK1 stability and drives triple-negative breast cancer tumorigenesis.
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DOI：
10.1186/s13046-023-02781-3
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发表时间：
2023-09-04
影响因子：
11.3
通讯作者：
Zhang, Chunlei
中科院分区：
文献类型：
--
作者：
Han, Zhitao;Jia, Qi;Zhang, Jing;Chen, Miaomiao;Wang, Lining;Tong, Kai;He, Weiwei;Zhang, Yajie;Zhu, Weina;Qin, Ju;Wang, Tao;Liu, Tielong;Ma, Yong;Chen, Yuanming;Zha, Siluo;Zhang, Chunlei
关键词：
越来越多的证据表明，去泛素化酶的异常表达与三阴性乳腺癌（TNBC）的发生和发展有关。公开可用的乳腺癌数据TCGA数据库用于分析OTUD去泛素化家族成员，这些成员与乳腺癌和卵巢肿瘤结构域2（OTUD-2）或YOD 1的生存相关。本研究的目的是评估YOD 1在人TNBC中的表达和功能，然后探索潜在的分子事件。采用qRT-PCR、Western blot和免疫组化方法检测32例TNBC和44例NTNBC中YOD 1的表达。使用集落形成测定、transwell测定、CCK 8测定、TUNEL测定、流式细胞术分析和异种移植肿瘤测定，在体外和体内评估YOD 1表达的操纵对TNBC细胞增殖、迁移、侵袭、细胞周期和药物抗性的影响。接下来，进行蛋白质组学分析、蛋白质印迹、邻位连接测定、免疫沉淀和免疫荧光以评估下游靶标。结果发现，与非三阴性乳腺癌（NTNBC）相比，YOD 1在TNBC组织中显著上调，这与TNBC患者的不良生存率正相关。YOD 1基因的敲除有效抑制了TNBC细胞的迁移、增殖、细胞周期以及对顺铂和紫杉醇的耐药性。从机制上讲，YOD 1通过与CDK 1结合，以依赖于其催化活性的方式促进TNBC进展，导致CDK 1的去聚泛素化和CDK 1表达上调。此外，发现YOD 1过表达与人TNBC标本中的CDK 1过表达相关。最后，体内研究表明，YOD 1敲低或YOD 1抑制剂可以抑制CDK 1表达，抑制TNBC肿瘤的生长和转移。我们的研究强调了YOD 1通过与CDK 1结合并介导其稳定性和致癌活性在TNBC中作为致癌基因发挥作用。干扰YOD 1表达或抑制YOD 1可抑制TNBC细胞在体外和体内，表明YOD 1可能被证明是一个有前途的治疗靶点TNBC。在线版本包含补充材料，可通过10.1186/s13046-023-02781-3获得。
Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with the initiation and progression of Triple-negative breast cancer (TNBC). The publicly available TCGA database of breast cancer data was used to analyze the OTUD deubiquitinating family members that were correlated with survival of breast cancer and ovarian tumor domain-containing 2 (OTUD-2), or YOD1 was identified. The aim of present study was to assess YOD1 expression and function in human TNBC and then explored the underlying molecular events. We detected the expression of YOD1 in 32 TNBC and 44 NTNBC samples by qRT-PCR, Western blot and immunohistochemistry. Manipulation of YOD1 expression was assessed in vitro and in vivo for TNBC cell proliferation, migration, invasion, cell-cycle and drug resistance, using colony formation assay, transwell assay, CCK8 assay, TUNEL assay, flow cytometric analysis and xenograft tumor assay. Next, proteomic analysis, Western blot, proximity ligation assay, Immunoprecipitation, and Immunofluorescence were conducted to assess downstream targets. It was found that YOD1 was significantly upregulated in TNBC tissues compared with non-triple-negative breast cancer (NTNBC), which was positively correlated with poor survival in TNBC patients. Knockdown of YOD1 effectively inhibited TNBC cell migration, proliferation, cell cycle and resistance to cisplatin and paclitaxel. Mechanistically, YOD1 promoted TNBC progression in a manner dependent on its catalytic activity through binding with CDK1, leading to de-polyubiquitylation of CDK1 and upregulation of CDK1 expression. In addition, YOD1 overexpression was found to be correlated with CDK1 overexpression in human TNBC specimens. Finally, in vivo study demonstrated that YOD1 knockdown or YOD1 inhibitor could inhibit CDK1 expression and suppress the growth and metastasis of TNBC tumors. Our study highlights that YOD1 functions as an oncogene in TNBC via binding to CDK1 and mediated its stability and oncogenic activity. Interfering with YOD1 expression or YOD1 inhibitor could suppress TNBC cells in vitro and in vivo, suggesting that YOD1 may prove to be a promising therapeutic target for TNBC. The online version contains supplementary material available at 10.1186/s13046-023-02781-3.
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DOI：
10.1146/annurev-pathol-042420-093238
发表时间：
2022-01-24
期刊：
Annual review of pathology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1002/advs.202004504
发表时间：
2021-08
期刊：
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
影响因子：
--
作者：
Gong Z;Li A;Ding J;Li Q;Zhang L;Li Y;Meng Z;Chen F;Huang J;Zhou D;Hu R;Ye J;Liu W;You H
通讯作者：
You H
影响因子：
7.7
作者：
Schimmack, Gisela;schorpp, kenji;Krappmann, Daniel
通讯作者：
Krappmann, Daniel
PDL1 和 LDHA 通过调节 miR-34a 在三阴性乳腺癌中充当 ceRNA
DOI：
10.1186/s13046-017-0593-2
发表时间：
2017-09-15
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
--
作者：
Huang X;Xie X;Wang H;Xiao X;Yang L;Tian Z;Guo X;Zhang L;Tang H;Xie X
通讯作者：
Xie X
影响因子：
16
作者：
Ernst, Robert;Mueller, Britta;Ploegh, Hidde L.;Schlieker, Christian
通讯作者：
Schlieker, Christian