Identification of a Novel Substrate for eEF2K and the AURKA-SOX8 as the Related Pathway in TNBC

Xiaoya Wan; Rong Gong; Xiaobao Zhao; Yizhi Li; Tianjiao Shan; Changxin Zhong; Rongfeng Zhu; Zonglin Chen; Shilong Jiang; Linhao He; Shijun Cao; Sheng Tian; Jinming Yang; Na Ye; Wenjun Yi; Yan Cheng

doi:10.1002/advs.202412985

Identification of a Novel Substrate for eEF2K and the AURKA-SOX8 as the Related Pathway in TNBC

Xiaoya Wan, Rong Gong, Xiaobao Zhao, Yizhi Li, Tianjiao Shan, Changxin Zhong, Rongfeng Zhu, Zonglin Chen, Shilong Jiang, Linhao He, Shijun Cao, Sheng Tian, Jinming Yang, Na Ye, Wenjun Yi, Yan Cheng

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

Eukaryotic elongation factor 2 kinase (eEF2K) has been considered as a putative target for cancer therapy; however, the underlying mechanisms of eEF2K in triple-negative breast cancer (TNBC) progression remain to be fully elucidated. In this study, it is shown that eEF2K is highly expressed in TNBC and is associated with poor prognosis. In vitro, in vivo, and patient-derived organoid experiments demonstrate that knockdown of eEF2K significantly impedes progression of TNBC. Proteomic analysis and confirmation experiments reveal that eEF2K positively regulates the mRNA and protein expressions of sex-determining region Y-box 8 (SOX8). Mechanistically, eEF2K binds to and phosphorylates aurora kinase A (AURKA) at S391, a newly identified phosphorylation site critical for maintaining AURKA protein stability and kinase activity. Moreover, the compound C1, a molecular glue to degrade eEF2K, is optimized by designing and synthesizing its derivatives using reasonable structure-based optimization approach. The new compound C4 shows better ability to degrade eEF2K and stronger anti-cancer activity than C1. These findings not only uncover the pivotal role of the eEF2K/AURKA/SOX8 axis in TNBC progression, but also provide a promising lead compound for developing novel drug for treatment of TNBC.

Original language	English
Article number	2412985
Journal	Advanced Science
Volume	12
Issue number	14
DOIs	https://doi.org/10.1002/advs.202412985
State	Published - Apr 10 2025

Bibliographical note

Publisher Copyright:
© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH.

Funding

The authors thank Zhongyuan Xiang from the clinical laboratory of the Second Xiangya Hospital of Central South University for offering serum biochemical index detection services. This study was funded by the National Natural Science Foundation of China (Project No. 82373064 and 81972480 for Y.C.; No. 22477093 and 22177086 for N. Y.), Hunan Provincial Natural Science Foundation (Project No. 2022JJ80106 for Y.C.), the Project of Innovation-driven Plan in Central South University (1053320221775 for X.W.). The authors thank Zhongyuan Xiang from the clinical laboratory of the Second Xiangya Hospital of Central South University for offering serum biochemical index detection services. This study was funded by the National Natural Science Foundation of China (Project No. 82373064 and 81972480 for Y.C.; No. 22477093 and 22177086 for N. Y.), Hunan Provincial Natural Science Foundation (Project No. 2022JJ80106 for Y.C.), the Project of Innovation\u2010driven Plan in Central South University (1053320221775 for X.W.).

Funders	Funder number
Second Xiangya Hospital of Central South University
Natural Science Foundation of Hunan Province, China	2022JJ80106
Natural Science Foundation of Hunan Province, China
National Natural Science Foundation of China (NSFC)	81972480, 82373064, 22477093, 22177086
National Natural Science Foundation of China (NSFC)
Central South University	1053320221775
Central South University

Keywords

AURKA
SOX8
eEF2K
eEF2K degrader
triple-negative breast cancer

ASJC Scopus subject areas

Medicine (miscellaneous)
General Chemical Engineering
General Materials Science
Biochemistry, Genetics and Molecular Biology (miscellaneous)
General Engineering
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/advs.202412985

Cite this

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title = "Identification of a Novel Substrate for eEF2K and the AURKA-SOX8 as the Related Pathway in TNBC",

abstract = "Eukaryotic elongation factor 2 kinase (eEF2K) has been considered as a putative target for cancer therapy; however, the underlying mechanisms of eEF2K in triple-negative breast cancer (TNBC) progression remain to be fully elucidated. In this study, it is shown that eEF2K is highly expressed in TNBC and is associated with poor prognosis. In vitro, in vivo, and patient-derived organoid experiments demonstrate that knockdown of eEF2K significantly impedes progression of TNBC. Proteomic analysis and confirmation experiments reveal that eEF2K positively regulates the mRNA and protein expressions of sex-determining region Y-box 8 (SOX8). Mechanistically, eEF2K binds to and phosphorylates aurora kinase A (AURKA) at S391, a newly identified phosphorylation site critical for maintaining AURKA protein stability and kinase activity. Moreover, the compound C1, a molecular glue to degrade eEF2K, is optimized by designing and synthesizing its derivatives using reasonable structure-based optimization approach. The new compound C4 shows better ability to degrade eEF2K and stronger anti-cancer activity than C1. These findings not only uncover the pivotal role of the eEF2K/AURKA/SOX8 axis in TNBC progression, but also provide a promising lead compound for developing novel drug for treatment of TNBC.",

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author = "Xiaoya Wan and Rong Gong and Xiaobao Zhao and Yizhi Li and Tianjiao Shan and Changxin Zhong and Rongfeng Zhu and Zonglin Chen and Shilong Jiang and Linhao He and Shijun Cao and Sheng Tian and Jinming Yang and Na Ye and Wenjun Yi and Yan Cheng",

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doi = "10.1002/advs.202412985",

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AU - Gong, Rong

AU - Zhao, Xiaobao

AU - Li, Yizhi

AU - Shan, Tianjiao

AU - Zhong, Changxin

AU - Zhu, Rongfeng

AU - Chen, Zonglin

AU - Jiang, Shilong

AU - He, Linhao

AU - Cao, Shijun

AU - Tian, Sheng

AU - Yang, Jinming

AU - Ye, Na

AU - Yi, Wenjun

AU - Cheng, Yan

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Identification of a Novel Substrate for eEF2K and the AURKA-SOX8 as the Related Pathway in TNBC

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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