中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
首页 机构 成果 学者
  
  1. CAS IR Grid
  2. 上海药物研究所
  3. 中国科学院上海药物研究所
  4. 新药研究国家重点实验室
HSP90 N-terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2-driven breast cancer progression

文献类型：期刊论文

作者Yang, Fan1,2,3,9,10; Sun, Rui9,10; Hou, Zeng4,5,6; Zhang, Fang-Lin9,10; Xiao, Yi1,2,3,9,10; Yang, Yun-Song1,2,3,9,10; Yang, Shao-Ying9,10; Xie, Yi-Fan1,2,3,9,10; Liu, Ying-Ying1,2,3,9,10; Luo, Cheng4,5,6
刊名CLINICAL AND TRANSLATIONAL MEDICINE
出版日期2022-05-01
卷号12期号:5页码:18
关键词breast cancer chaperone-mediated autophagy HSP90 inhibitor MORC2 protein degradation
ISSN号2001-1326
DOI10.1002/ctm2.825
通讯作者Liu, Guang-Yu(liugy688@163.com) ; Shao, Zhi-Min(zhimingshao@yahoo.com) ; Li, Da-Qiang(daqiangli1974@fudan.edu.cn)
英文摘要Aims MORC family CW-type zinc finger 2 (MORC2), a GHKL-type ATPase, is aberrantly upregulated in multiple types of human tumors with profound effects on cancer aggressiveness, therapeutic resistance, and clinical outcome, thus making it an attractive drug target for anticancer therapy. However, the antagonists of MORC2 have not yet been documented. Methods and Results We report that MORC2 is a relatively stable protein, and the N-terminal homodimerization but not ATP binding and hydrolysis is crucial for its stability through immunoblotting analysis and Quantitative real-time PCR. The N-terminal but not C-terminal inhibitors of heat shock protein 90 (HSP90) destabilize MORC2 in multiple cancer cell lines, and strikingly, this process is independent on HSP90. Mechanistical investigations revealed that HSP90 N-terminal inhibitors disrupt MORC2 homodimer formation without affecting its ATPase activities, and promote its lysosomal degradation through the chaperone-mediated autophagy pathway. Consequently, HSP90 inhibitor 17-AAG effectively blocks the growth and metastatic potential of MORC2-expressing breast cancer cells both in vitro and in vivo, and these noted effects are not due to HSP90 inhibition. Conclusion We uncover a previously unknown role for HSP90 N-terminal inhibitors in promoting MORC2 degradation in a HSP90-indepentent manner and support the potential application of these inhibitors for treating MORC2-overexpressing tumors, even those with low or absent HSP90 expression. These results also provide new clue for further design of novel small-molecule inhibitors of MORC2 for anticancer therapeutic application.
WOS关键词TANESPIMYCIN 17-AAG ; ANTITUMOR-ACTIVITY ; HEAT-SHOCK-PROTEIN-90 ; DIMERIZATION ; DYNAMICS ; PHOSPHORYLATION ; TRASTUZUMAB ; ACETYLATION ; METASTASIS ; MUTATIONS
资助项目National Natural Science Foundation of China[81772805] ; National Natural Science Foundation of China[81972461] ; National Natural Science Foundation of China[82173275] ; National Key R&D Program of China[2017YFC0908400] ; National Key R&D Program of China[2018YFE0201600]
WOS研究方向Oncology ; Research & Experimental Medicine
语种英语
WOS记录号WOS:000791503300001
出版者JOHN WILEY & SONS LTD
源URL[http://119.78.100.183/handle/2S10ELR8/299363]  
专题新药研究国家重点实验室
通讯作者Liu, Guang-Yu; Shao, Zhi-Min; Li, Da-Qiang
作者单位1.Fudan Univ, Shanghai Med Coll, Canc Inst, Shanghai, Peoples R China
2.Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China
3.Fudan Univ, Shanghai Med Coll, Dept Breast Surg, Shanghai, Peoples R China
4.UCAS, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China
5.Chinese Acad Sci, Drug Discovery & Design Ctr, Ctr Chem Biol, State Key Lab Drug Res,Shanghai Inst Mat Med, Shanghai, Peoples R China
6.Univ Chinese Acad Sci, Dept Pharm, Beijing, Peoples R China
7.Fudan Univ, Shanghai Med Coll, Shanghai Key Lab Radiat Oncol, Shanghai, Peoples R China
8.Fudan Univ, Shanghai Med Coll, Shanghai Key Lab Breast Canc, Shanghai, Peoples R China
9.Fudan Univ, Shanghai Canc Ctr, Shanghai 200032, Peoples R China
10.Fudan Univ, Shanghai Key Lab Med Epigenet, Int Colab Med Epigenet & Metab, Minist Sci & Technol,Inst Biomed Sci, Shanghai 200032, Peoples R China
推荐引用方式
GB/T 7714		 Yang, Fan,Sun, Rui,Hou, Zeng,et al. HSP90 N-terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2-driven breast cancer progression[J]. CLINICAL AND TRANSLATIONAL MEDICINE,2022,12(5):18.
APA Yang, Fan.,Sun, Rui.,Hou, Zeng.,Zhang, Fang-Lin.,Xiao, Yi.,...&Li, Da-Qiang.(2022).HSP90 N-terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2-driven breast cancer progression.CLINICAL AND TRANSLATIONAL MEDICINE,12(5),18.
MLA Yang, Fan,et al."HSP90 N-terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2-driven breast cancer progression".CLINICAL AND TRANSLATIONAL MEDICINE 12.5(2022):18.

入库方式： OAI收割

来源：上海药物研究所

浏览0
下载0
收藏0
其他版本

除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。