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

被引：8

作者：

Hu, Shu-Yuan ^{[1
,2
]}

Qian, Jin-Xian ^{[3
]}

Yang, Shao-Ying ^{[4
]}

Andriani, Lisa ^{[3
]}

Liao, Li ^{[4
]}

Deng, Ling ^{[1
,2
]}

Huang, Min-Ying ^{[1
,2
]}

Zhang, Yin-Ling ^{[4
]}

Zhang, Fang-Lin ^{[4
,8
]}

Shao, Zhi-Min ^{[1
,2
,3
,4
,5
,6
,7
,9
,10
]}

Li, Da-Qiang ^{[1
,2
,3
,4
,5
,6
,7
,9
,10
]}

机构：

[1] Fudan Univ, Shanghai Canc Ctr, Shanghai, Peoples R China

[2] Fudan Univ, Inst Biomed Sci, Shanghai Med Coll, Shanghai, Peoples R China

[3] Fudan Univ, Shanghai Med Coll, Dept Breast Surg, Shanghai, Peoples R China

[4] Fudan Univ, Canc Inst, Shanghai Med Coll, Shanghai, Peoples R China

[5] Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai, Peoples R China

[6] Fudan Univ, Shanghai Med Coll, Shanghai Key Lab Breast Canc, Shanghai, Peoples R China

[7] Fudan Univ, Shanghai Med Coll, Shanghai Key Lab Radiat Oncol, Shanghai, Peoples R China

[8] Fudan Univ, Canc Inst, Shanghai Med Coll, Shanghai Canc Ctr, Shanghai 200032, Peoples R China

[9] Fudan Univ, Dept Breast Surg, Shanghai 200032, Peoples R China

[10] Fudan Univ, Canc Inst, Shanghai Med Coll, Shanghai Canc Ctr, Shanghai 200032, Peoples R China

来源：

CLINICAL AND TRANSLATIONAL MEDICINE | 2023年 / 13卷 / 03期

基金：

中国国家自然科学基金; 上海市自然科学基金;

关键词：

chaperone-mediated autophagy; cyclin-dependent kinase 1; microtubule-targeting agents; mitotic arrest; MORC2; spindle assembly checkpoint; SPINDLE-ASSEMBLY CHECKPOINT; MARIE-TOOTH DISEASE; MORC2; RESISTANCE; PHOSPHORYLATION; MUTATIONS; STABILITY; CELLS; IDENTIFICATION; INACTIVATION;

D O I：

10.1002/ctm2.1210

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

BackgroundMicrotubule-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. MethodsImmunoblotting 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. ResultsHere, 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. ConclusionsCollectively, 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.

引用

页数：21