Zinc-finger protein CXXC5 promotes breast carcinogenesis by regulating the TSC1/mTOR signaling pathway.
Zinc-finger protein CXXC5 promotes breast carcinogenesis by regulating the TSC1/mTOR signaling pathway.
复制标题
锌指蛋白 CXXC5 通过调节 TSC1/mTOR 信号通路促进乳腺癌发生
DOI：
10.1016/j.jbc.2022.102812
复制
发表时间：
2023-01
影响因子：
4.8
通讯作者：
Shan, Lin
中科院分区：
文献类型：
--
作者：
Wang, Wenjuan;Zhang, Zhaohan;Zhao, Minghui;Wang, Yu;Ge, Yuze;Shan, Lin
CXXC 5是锌指蛋白CXXC家族的成员，与许多病理过程相关。然而，CXXC 5的病理生理功能尚未明确。在此，我们发现CXXC 5与CRL 4 B和NuRD复合物相互作用。通过下一代测序筛选CXXC 5-CRL 4 B-NuRD复合物下游的转录靶标（染色质免疫沉淀测序）揭示了该复合物调节一组基因（包括TSC 1）的转录抑制过程（结节性硬化症复合物亚基1），其在细胞生长和哺乳动物雷帕霉素靶信号通路调节中起重要作用，并且其异常调节导致程序性细胞死亡配体蛋白1（PD-L1）的活化。有趣的是，CXXC 5表达在维生素B2刺激后增加，但在维生素D治疗后减少。我们还发现CXXC 5-CRL 4 B-NuRD复合物在体外促进肿瘤细胞的增殖，并在体内加速乳腺癌的生长。CXXC 5、CUL 4 B和MTA 1在乳腺癌发生发展过程中表达增强，相应地TSC 1表达减弱。同时，CXXC 5的高表达与肿瘤的组织学分级、恶性程度及患者的生存率呈正相关。总之，我们的研究表明，CXXC 5介导的TSC 1抑制激活雷帕霉素途径的哺乳动物靶点，减少自噬细胞死亡，诱导PD-L1介导的免疫抑制，并导致肿瘤的发展，阐明了CXXC 5的病理生理功能的机制。
CXXC5, a member of the CXXC family of zinc-finger proteins, is associated with numerous pathological processes. However, the pathophysiological function of CXXC5 has not been clearly established. Herein, we found that CXXC5 interacts with the CRL4B and NuRD complexes. Screening of transcriptional targets downstream of the CXXC5–CRL4B–NuRD complex by next-generation sequencing (chromatin immunoprecipitation sequencing) revealed that the complex regulates the transcriptional repression process of a cohort of genes, including TSC1 (tuberous sclerosis complex subunit 1), which play important roles in cell growth and mammalian target of rapamycin signaling pathway regulation, and whose abnormal regulation results in the activation of programmed cell death–ligand protein 1 (PD-L1). Intriguingly, CXXC5 expression increased after stimulation with vitamin B2 but decreased after vitamin D treatment. We also found that the CXXC5–CRL4B–NuRD complex promotes the proliferation of tumor cells in vitro and accelerates the growth of breast cancer in vivo. The expression of CXXC5, CUL4B, and MTA1 increased during the occurrence and development of breast cancer, and correspondingly, TSC1 expression decreased. Meanwhile, a high expression of CXXC5 was positively correlated with the histological grade of high malignancy and poor survival of patients. In conclusion, our study revealed that CXXC5-mediated TSC1 suppression activates the mammalian target of rapamycin pathway, reduces autophagic cell death, induces PD-L1-mediated immune suppression, and results in tumor development, shedding light on the mechanism of the pathophysiological function of CXXC5.
登录
查看更多内容
影响因子：
3.3
作者：
Hamanishi J;Mandai M;Matsumura N;Abiko K;Baba T;Konishi I
通讯作者：
Konishi I
DOI：
10.1016/j.ecl.2013.02.004
发表时间：
2013-06
影响因子：
4.5
作者：
Gallagher, J. Christopher
通讯作者：
Gallagher, J. Christopher
影响因子：
50.5
作者：
Knappskog, S.;Myklebust, L. M.;Pendino, F.
通讯作者：
Pendino, F.
影响因子：
20.3
作者：
Kuehnl, Andrea;Valk, Peter J. M.;Grimwade, David
通讯作者：
Grimwade, David
影响因子：
14.2
作者：
Joshi, Hemant R.;Hill, Harry R.;Kumanovics, Attila
通讯作者：
Kumanovics, Attila