Stabilization of Pin1 by USP34 promotes Ubc9 isomerization and protein sumoylation in glioma stem cells

Qiuhong Zhu, Panpan Liang, Hao Meng, Fangzhen Li, Wei Miao, Cuiying Chu, Wei Wang, Dongxue Li, Cong Chen, Yu Shi, Xingjiang Yu, Yifang Ping, Chaoshi Niu, Hai-bo Wu, Aili Zhang (), Xiu-wu Bian () and Wenchao Zhou ()
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Qiuhong Zhu: University of Science and Technology of China
Panpan Liang: University of Science and Technology of China
Hao Meng: University of Science and Technology of China
Fangzhen Li: University of Science and Technology of China
Wei Miao: University of Science and Technology of China
Cuiying Chu: University of Science and Technology of China
Wei Wang: University of Science and Technology of China
Dongxue Li: University of Science and Technology of China
Cong Chen: University of Science and Technology of China
Yu Shi: Southwest Hospital, Third Military Medical University (Army Medical University) and Key Laboratory of Tumor Immunopathology, Ministry of Education of China
Xingjiang Yu: Huazhong University of Science and Technology
Yifang Ping: University of Science and Technology of China
Chaoshi Niu: University of Science and Technology of China
Hai-bo Wu: University of Science and Technology of China
Aili Zhang: Anhui Medical University
Xiu-wu Bian: University of Science and Technology of China
Wenchao Zhou: University of Science and Technology of China

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract The peptidyl-prolyl cis-trans isomerase Pin1 is a pivotal therapeutic target in cancers, but the regulation of Pin1 protein stability is largely unknown. High Pin1 expression is associated with SUMO1-modified protein hypersumoylation in glioma stem cells (GSCs), but the underlying mechanisms remain elusive. Here we demonstrate that Pin1 is deubiquitinated and stabilized by USP34, which promotes isomerization of the sole SUMO E2 enzyme Ubc9, leading to SUMO1-modified hypersumoylation to support GSC maintenance. Pin1 interacts with USP34, a deubiquitinase with preferential expression and oncogenic function in GSCs. Such interaction is facilitated by Plk1-mediated phosphorylation of Pin1. Disruption of USP34 or inhibition of Plk1 promotes poly-ubiquitination and degradation of Pin1. Furthermore, Pin1 isomerizes Ubc9 to upregulate Ubc9 thioester formation with SUMO1, which requires CDK1-mediated phosphorylation of Ubc9. Combined inhibition of Pin1 and CDK1 with sulfopin and RO3306 most effectively suppresses orthotopic tumor growth. Our findings provide multiple molecular targets to induce Pin1 degradation and suppress hypersumoylation for cancer treatment.

Date: 2024
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DOI: 10.1038/s41467-023-44349-x

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