Targeting CRL4 suppresses chemoresistant ovarian cancer growth by inducing mitophagy

Yang Meng; Lei Qiu; Xinyi Zeng; Xiaoyan Hu; Yaguang Zhang; Xiaowen Wan; Xiaobing Mao; Jian Wu; Yongfeng Xu; Qunli Xiong; Zhixin Chen; Bo Zhang; Junhong Han

doi:10.1038/s41392-022-01253-y

Signal Transduction and Targeted Therapy (Dec 2022)

Targeting CRL4 suppresses chemoresistant ovarian cancer growth by inducing mitophagy

Yang Meng,
Lei Qiu,
Xinyi Zeng,
Xiaoyan Hu,
Yaguang Zhang,
Xiaowen Wan,
Xiaobing Mao,
Jian Wu,
Yongfeng Xu,
Qunli Xiong,
Zhixin Chen,
Bo Zhang,
Junhong Han

Affiliations

Yang Meng: Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Lei Qiu: Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Xinyi Zeng: Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Xiaoyan Hu: Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University
Yaguang Zhang: Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Xiaowen Wan: Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Xiaobing Mao: Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Jian Wu: Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Yongfeng Xu: Abdominal Oncology Ward, Cancer Center, West China Hospital of Sichuan University
Qunli Xiong: Abdominal Oncology Ward, Cancer Center, West China Hospital of Sichuan University
Zhixin Chen: Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Bo Zhang: Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University
Junhong Han: Research Laboratory of Tumor Epigenetics and Genomics, Department of General Surgery, Frontiers Science Center for Disease-related Molecular Network and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University

DOI: https://doi.org/10.1038/s41392-022-01253-y
Journal volume & issue: Vol. 7, no. 1
pp. 1 – 16

Abstract

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Abstract Chemoresistance has long been the bottleneck of ovarian cancer (OC) prognosis. It has been shown that mitochondria play a crucial role in cell response to chemotherapy and that dysregulated mitochondrial dynamics is intricately linked with diseases like OC, but the underlying mechanisms remain equivocal. Here, we demonstrate a new mechanism where CRL4CUL4A/DDB1 manipulates OC cell chemoresistance by regulating mitochondrial dynamics and mitophagy. CRL4CUL4A/DDB1 depletion enhanced mitochondrial fission by upregulating AMPKαThr172 and MFFSer172/Ser146 phosphorylation, which in turn recruited DRP1 to mitochondria. CRL4CUL4A/DDB1 loss stimulated mitophagy through the Parkin-PINK1 pathway to degrade the dysfunctional and fragmented mitochondria. Importantly, CRL4CUL4A/DDB1 loss inhibited OC cell proliferation, whereas inhibiting autophagy partially reversed this disruption. Our findings provide novel insight into the multifaceted function of the CRL4 E3 ubiquitin ligase complex in regulating mitochondrial fission, mitophagy, and OC chemoresistance. Disruption of CRL4CUL4A/DDB1 and mitophagy may be a promising therapeutic strategy to overcome chemoresistance in OC.

Published in Signal Transduction and Targeted Therapy

ISSN: 2059-3635 (Online)
Publisher: Nature Publishing Group
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: http://www.nature.com/sigtrans/

About the journal