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HSP90 N‐terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2‐driven breast cancer progression
Author(s) -
Yang Fan,
Sun Rui,
Hou Zeng,
Zhang FangLin,
Xiao Yi,
Yang YunSong,
Yang ShaoYing,
Xie YiFan,
Liu YingYing,
Luo Cheng,
Liu GuangYu,
Shao ZhiMin,
Li DaQiang
Publication year - 2022
Publication title -
clinical and translational medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.125
H-Index - 1
ISSN - 2001-1326
DOI - 10.1002/ctm2.825
Subject(s) - hsp90 , autophagy , zinc finger , cancer cell , cancer research , heat shock protein , protein degradation , chemistry , cancer , microbiology and biotechnology , apoptosis , biochemistry , biology , transcription factor , genetics , gene
Abstract 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.

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