Cargando…
HSP90 N‐terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2‐driven breast cancer progression
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076019/ https://www.ncbi.nlm.nih.gov/pubmed/35522895 http://dx.doi.org/10.1002/ctm2.825 |
_version_ | 1784701817855148032 |
---|---|
author | Yang, Fan Sun, Rui Hou, Zeng Zhang, Fang‐Lin Xiao, Yi Yang, Yun‐Song Yang, Shao‐Ying Xie, Yi‐Fan Liu, Ying‐Ying Luo, Cheng Liu, Guang‐Yu Shao, Zhi‐Min Li, Da‐Qiang |
author_facet | Yang, Fan Sun, Rui Hou, Zeng Zhang, Fang‐Lin Xiao, Yi Yang, Yun‐Song Yang, Shao‐Ying Xie, Yi‐Fan Liu, Ying‐Ying Luo, Cheng Liu, Guang‐Yu Shao, Zhi‐Min Li, Da‐Qiang |
author_sort | Yang, Fan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9076019 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90760192022-05-13 HSP90 N‐terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2‐driven breast cancer progression Yang, Fan Sun, Rui Hou, Zeng Zhang, Fang‐Lin Xiao, Yi Yang, Yun‐Song Yang, Shao‐Ying Xie, Yi‐Fan Liu, Ying‐Ying Luo, Cheng Liu, Guang‐Yu Shao, Zhi‐Min Li, Da‐Qiang Clin Transl Med Research Articles 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. John Wiley and Sons Inc. 2022-05-06 /pmc/articles/PMC9076019/ /pubmed/35522895 http://dx.doi.org/10.1002/ctm2.825 Text en © 2022 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Yang, Fan Sun, Rui Hou, Zeng Zhang, Fang‐Lin Xiao, Yi Yang, Yun‐Song Yang, Shao‐Ying Xie, Yi‐Fan Liu, Ying‐Ying Luo, Cheng Liu, Guang‐Yu Shao, Zhi‐Min Li, Da‐Qiang HSP90 N‐terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2‐driven breast cancer progression |
title | HSP90 N‐terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2‐driven breast cancer progression |
title_full | HSP90 N‐terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2‐driven breast cancer progression |
title_fullStr | HSP90 N‐terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2‐driven breast cancer progression |
title_full_unstemmed | HSP90 N‐terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2‐driven breast cancer progression |
title_short | HSP90 N‐terminal inhibitors target oncoprotein MORC2 for autophagic degradation and suppress MORC2‐driven breast cancer progression |
title_sort | hsp90 n‐terminal inhibitors target oncoprotein morc2 for autophagic degradation and suppress morc2‐driven breast cancer progression |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9076019/ https://www.ncbi.nlm.nih.gov/pubmed/35522895 http://dx.doi.org/10.1002/ctm2.825 |
work_keys_str_mv | AT yangfan hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression AT sunrui hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression AT houzeng hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression AT zhangfanglin hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression AT xiaoyi hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression AT yangyunsong hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression AT yangshaoying hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression AT xieyifan hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression AT liuyingying hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression AT luocheng hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression AT liuguangyu hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression AT shaozhimin hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression AT lidaqiang hsp90nterminalinhibitorstargetoncoproteinmorc2forautophagicdegradationandsuppressmorc2drivenbreastcancerprogression |