Neddylation inhibition induces glutamine uptake and metabolism by targeting CRL3SPOP E3 ligase in cancer cells

Qiyin Zhou, Wenyu Lin, Chaoqun Wang, Fei Sun, Siwei Ju, Qian Chen, Yi Wang, Yongxia Chen, Haomin Li, Linbo Wang, Zeping Hu, Hongchuan Jin, Xian Wang () and Yi Sun ()
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Qiyin Zhou: Zhejiang University School of Medicine
Wenyu Lin: Zhejiang University School of Medicine
Chaoqun Wang: Zhejiang University School of Medicine
Fei Sun: Tsinghua University
Siwei Ju: Zhejiang University
Qian Chen: Zhejiang University School of Medicine
Yi Wang: Tsinghua University
Yongxia Chen: Zhejiang University
Haomin Li: Zhejiang University School of Medicine, National Clinical Research Center for Child Health
Linbo Wang: Zhejiang University
Zeping Hu: Tsinghua University
Hongchuan Jin: Zhejiang University School of Medicine
Xian Wang: Zhejiang University School of Medicine
Yi Sun: Zhejiang University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Abnormal neddylation activation is frequently observed in human cancers and neddylation inhibition has been proposed as a therapy for cancer. Here, we report that MLN4924, a small-molecule inhibitor of neddylation activating enzyme, increases glutamine uptake in breast cancer cells by causing accumulation of glutamine transporter ASCT2/SLC1A5, via inactivation of CRL3-SPOP E3 ligase. We show the E3 ligase SPOP promotes ASCT2 ubiquitylation, whereas SPOP itself is auto-ubiquitylated upon glutamine deprivation. Thus, SPOP and ASCT2 inversely regulate glutamine uptake and metabolism. SPOP knockdown increases ASCT2 levels to promote growth which is rescued by ASCT2 knockdown. Adding ASCT2 inhibitor V-9302 enhances MLN4924 suppression of tumor growth. In human breast cancer specimens, SPOP and ASCT2 levels are inversely correlated, whereas lower SPOP with higher ASCT2 predicts a worse patient survival. Collectively, our study links neddylation to glutamine metabolism via the SPOP-ASCT2 axis and provides a rational drug combination for enhanced cancer therapy.

Date: 2022
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DOI: 10.1038/s41467-022-30559-2

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