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SIRT1 deacetylates WEE1 and sensitizes cancer cells to WEE1 inhibition.

Author information

Affiliations

  • 1. Department of Cell Biology, and Department of General Surgery of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
      Authors
    • Zhu X 1, 2
    • Su Q 1
    • Xie H 1
    • Liu T 1
    (4 authors)
  • 2. MOE Laboratory of Biosystems Homeostasis and Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
      Authors
    • Zhu X 1, 2
    • Song L 2
    • Huang J 2
    (3 authors)
  • 3. Department of Biophysics, and Kidney Disease Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
      Authors
    • Yang F 3
    (1 author)
  • 4. Department of Pathology, and Department of Medical Oncology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
      Authors
    • Zhang D 4
    • Wang B 4
    (2 authors)
  • 5. Zhejiang Provincial Key Laboratory of Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
      Authors
    • Lin S 5
    (1 author)
    • Show all (6)

ORCIDs linked to this article

Nature Chemical Biology, 12 Jan 2023, 19(5):585-595
https://doi.org/10.1038/s41589-022-01240-y PMID: 36635566 

Abstract 

The cell-cycle checkpoint kinase WEE1 is emerging as a therapeutic target for cancer treatment. However, how its catalytic activity is regulated remains poorly understood, and reliable biomarkers for predicting response to WEE1 inhibitor remain to be identified. Here we identify an evolutionarily conserved segment surrounding its Lys177 residue that inhibits WEE1 activity through an intermolecular interaction with the catalytic kinase domain. Upon DNA damage, CHK1-dependent phosphorylation of WEE1 at Ser642 primes GCN5-mediated acetylation at Lys177, resulting in dissociation of the inhibitory segment from the kinase domain and subsequent activation of WEE1 and cell-cycle checkpoints. Conversely, SIRT1 associates with and deacetylates WEE1, which maintains it in an inactive state. Consequently, SIRT1 deficiency induces WEE1 hyperacetylation and activation, rendering cancer cells resistant to WEE1 inhibition. These results suggest that SIRT1 expression level and abundance of WEE1 Lys177 acetylation in tumor cells can serve as useful biomarkers for predicting WEE1 inhibitor sensitivity or resistance.

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Read article at publisher's site: https://doi.org/10.1038/s41589-022-01240-y

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Funding 

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National Natural Science Foundation of China (2)