2. Academic Validation
  3. Neddylation inhibition induces glutamine uptake and metabolism by targeting CRL3SPOP E3 ligase in cancer cells

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

  • Nat Commun. 2022 May 31;13(1):3034. doi: 10.1038/s41467-022-30559-2.
Qiyin Zhou 1 2 3 4 5,  Wenyu Lin 2,  Chaoqun Wang 2 6,  Fei Sun 7,  Siwei Ju 8,  Qian Chen 1 4,  Yi Wang 7,  Yongxia Chen 8,  Haomin Li 9,  Linbo Wang 8,  Zeping Hu 7,  Hongchuan Jin 2 5,  Xian Wang  # 10 11 12,  Yi Sun  # 13 14 15 16
Affiliations

Affiliations

  • 1 Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China.
  • 2 Key Lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
  • 3 Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China.
  • 4 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, China.
  • 5 Cancer Center, Zhejiang University, Hangzhou, 310058, China.
  • 6 Department of Pathology, Affiliated Dongyang Hospital of Wenzhou Medical University, Dongyang, 322100, China.
  • 7 School of Pharmaceutical Sciences, Tsinghua-Peking Joint Center for Life Sciences, Beijing Frontier Research Center for Biological Structure, Tsinghua University, Beijing, 100084, China.
  • 8 Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, 310016, China.
  • 9 Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China.
  • 10 Key Lab of Biotherapy in Zhejiang, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China. wangx118@zju.edu.cn.
  • 11 Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China. wangx118@zju.edu.cn.
  • 12 Cancer Center, Zhejiang University, Hangzhou, 310058, China. wangx118@zju.edu.cn.
  • 13 Cancer Institute, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China. yisun@zju.edu.cn.
  • 14 Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, 310029, China. yisun@zju.edu.cn.
  • 15 Cancer Center, Zhejiang University, Hangzhou, 310058, China. yisun@zju.edu.cn.
  • 16 Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou, 310053, China. yisun@zju.edu.cn.
  • # Contributed equally.
PMID: 35641493 DOI: 10.1038/s41467-022-30559-2
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.

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