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

Targeting CRL4 suppresses chemoresistant ovarian cancer growth by inducing mitophagy

Signal Transduct Target Ther. 2022 Dec 9;7(1):388. doi: 10.1038/s41392-022-01253-y.

Authors

Yang Meng^#¹, Lei Qiu^#¹, Xinyi Zeng^{1

2}, Xiaoyan Hu³, Yaguang Zhang¹, Xiaowen Wan¹, Xiaobing Mao¹, Jian Wu¹, Yongfeng Xu⁴, Qunli Xiong⁴, Zhixin Chen¹, Bo Zhang¹, Junhong Han⁵

Affiliations

¹ 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, Chengdu, 610041, China.
² Division of Cancer Cell Biology, The Graduate School of Frontier Sciences, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
³ Division of Hematology/Oncology, Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
⁴ Abdominal Oncology Ward, Cancer Center, West China Hospital of Sichuan University, Chengdu, 610041, China.
⁵ 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, Chengdu, 610041, China. hjunhong@scu.edu.cn.

^# Contributed equally.

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 CRL4^CUL4A/DDB1 manipulates OC cell chemoresistance by regulating mitochondrial dynamics and mitophagy. CRL4^CUL4A/DDB1 depletion enhanced mitochondrial fission by upregulating AMPKα^Thr172 and MFF^{Ser172/Ser146} phosphorylation, which in turn recruited DRP1 to mitochondria. CRL4^CUL4A/DDB1 loss stimulated mitophagy through the Parkin-PINK1 pathway to degrade the dysfunctional and fragmented mitochondria. Importantly, CRL4^CUL4A/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 CRL4^CUL4A/DDB1 and mitophagy may be a promising therapeutic strategy to overcome chemoresistance in OC.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cullin Proteins
Drug Resistance, Neoplasm
Female
Humans
Mitophagy*
Ovarian Neoplasms* / drug therapy
Ovarian Neoplasms* / genetics

Substances

CUL4A protein, human
Cullin Proteins