Destabilization of microrchidia family CW-type zinc finger 2 via the cyclin-dependent kinase 1-chaperone-mediated autophagy pathway promotes mitotic arrest and enhances cancer cellular sensitivity to microtubule-targeting agents.

Publisher: Wiley Country of Publication: United States NLM ID: 101597971 Publication Model: Print Cited Medium: Internet ISSN: 2001-1326 (Electronic) Linking ISSN: 20011326 NLM ISO Abbreviation: Clin Transl Med Subsets: MEDLINE

Publication: 2020- : [Hoboken, NJ] : Wiley
Original Publication: Heidelberg : Springer-Verlag

Chaperone-Mediated Autophagy* ; Neoplasms* ; Transcription Factors*/genetics ; Transcription Factors*/metabolism; Humans ; CDC2 Protein Kinase/genetics ; CDC2 Protein Kinase/metabolism ; Cell Cycle Proteins/metabolism ; Microtubules/metabolism ; Mitosis/genetics ; Paclitaxel/pharmacology

Background: Microtubule-targeing agents (MTAs), such as paclitaxel (PTX) and vincristine (VCR), kill cancer cells through activtion of the spindle assembly checkpoint (SAC) and induction of mitotic arrest, but the development of resistance poses significant clinical challenges.
Methods: Immunoblotting and RT-qPCR were used to investigate potential function and related mechanism of MORC2. Flow cytometry analyses were carried out to determine cell cycle distribution and apoptosis. The effect of MORC2 on cellular sensitivity to PTX and VCR was determined by immunoblotting, flow cytometry, and colony formation assays. Immunoprecipitation assays and immunofluorescent staining were utilized to investigate protein-protein interaction and protein co-localization.
Results: Here, we identified microrchidia family CW-type zinc finger 2 (MORC2), a poorly characterized oncoprotein, as a novel regulator of SAC activation, mitotic progression, and resistance of cancer cells to PTX and VCR. Mechanically, PTX and VCR activate cyclin-dependent kinase 1, which in turn induces MORC2 phosphorylation at threonine 717 (T717) and T733. Phosphorylated MORC2 enhances its interation with HSPA8 and LAMP2A, two essential components of the chaperone-mediated autophagy (CMA) mechinery, resulting in its autophagic degradation. Degradation of MORC2 during mitosis leads to SAC activation through stabilizing anaphase promoting complex/cyclosome activator protein Cdc20 and facilitating mitotic checkpoint complex assembly, thus contributing to mitotic arrest induced by PTX and VCR. Notably, knockdown of MORC2 promotes mitotic arrest induced by PTX and VCR and enhances the sensitivity of cancer cells to PTX and VCR.
Conclusions: Collectively, these findings unveil a previously unrecognized function and regulatory mechanism of MORC2 in mitotic progression and resistance of cancer cells to MTAs. These results also provide a new clue for developing combined treatmentstrategy by targeting MORC2 in combination with MTAs against human cancer.
(© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

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Keywords: MORC2; chaperone-mediated autophagy; cyclin-dependent kinase 1; microtubule-targeting agents; mitotic arrest; spindle assembly checkpoint

EC 2.7.11.22 (CDC2 Protein Kinase)
0 (Cell Cycle Proteins)
0 (MORC2 protein, human)
P88XT4IS4D (Paclitaxel)
0 (Transcription Factors)

Date Created: 20230327 Date Completed: 20230329 Latest Revision: 20230406

20240829

PMC10040724

10.1002/ctm2.1210

36967563