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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Data availability
The authors declare that data supporting the findings of this study are available within the article, the accompanying source data files and the Supplementary Information. The pharmacogenomics dataset of 1,001 human cancer cell lines were obtained from the ArrayExpress database via the accession code E-MTAB-3610. Source data are provided with this paper.
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Acknowledgements
We thank all members of the Liu group for insightful discussions. This work was supported by National Key Research and Development Program of China (2022YFA1302800 and 2021YFA1101000 to T.L.), National Natural Science Foundation of China (31961160725, 31730021, and 31971220 to J.H., 32270769, 31970664, and 31822031 to T.L., 81970956 to M.W.), Zhejiang Science Foundation for Distinguished Young Scholars (LR18C070001 to T.L.), Fok Ying Tung Education Foundation, and Fundamental Research Funds for the Zhejiang Provincial Universities (2021XZZX039 to J.H.).
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X.Z., Q.S., H.X., and L.S. performed the cell biology, biochemistry, and xenograft experiments; F.Y. assisted with computational modeling; D.Z., B.W., S.L., J.H., and M.W. participated in experimental design and data analysis. T.L. designed and supervised the project and wrote the manuscript.
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Extended data
Extended Data Fig. 1 Correlation between the IC50 values of MK-1775 and SIRTs mRNA levels.
a–f, Two-sided P-values were determined using the relation between estimated coefficient and Student’s t distribution.
Extended Data Fig. 2 SIRT1 sensitizes cancer cells to WEE1 inhibitor MK-1775.
(a) Expression analysis of SIRT1 in different human cancer cell lines. (b–d) Knockdown of SIRT1 causes MK-1775 resistance. Cells infected with lentiviruses expressing control or SIRT1 shRNAs were treated with indicated doses of MK-1775 (0 nM, 50 nM, 100 nM, 150 nM, 300 nM, 600 nM, 800 nM, 1000 nM, 1200 nM, and 1500 nM for BxPC-3 cells; 0 nM, 50 nM, 100 nM, 150 nM, 300 nM, and 600 nM for PANC-1 and Capan-1 cells) for 48 hr or mock untreated. Cells were then shifted to fresh medium and permitted to grow for an additional 14 days before staining. Results shown are means of three independent experiments and were presented as means ± SEM. P-values were determined by two-way ANOVA. (e) Overexpression of SIRT1 sensitizes cells to MK-1775. BxPC-3 cells stably expressing Flag-tagged wild-type SIRT1 or the catalytic-inactive mutant were treated with indicated doses of MK-1775 (0 nM, 50 nM, 100 nM, 150 nM, 300 nM, and 600 nM) for 48 hr or mock untreated. Cells were then shifted to fresh medium and permitted to grow for an additional 14 days before staining. Results shown are means of three independent experiments and were presented as means ± SEM. P-values were determined by two-way ANOVA. (f–h) Cells infected with lentiviruses expressing control or SIRT1 shRNAs were treated with indicated doses of MK-1775 (0 nM, 50 nM, 100 nM, 150 nM, 300 nM, and 600 nM) for 48 hr or mock untreated. Cells were then shifted to fresh medium and permitted to grow for an additional 14 days before staining. Results shown are means of three independent experiments and were presented as means ± SEM. P-values were determined by two-way ANOVA.
Extended Data Fig. 3 SIRT1 depletion sensitizes cells to CPT.
MDA-MB-231 cells infected with lentiviruses expressing control or SIRT1 shRNAs were treated with indicated doses of CPT. Cells were then shifted to fresh medium and permitted to grow for an additional 14 days before staining. Results shown are means of three independent experiments and were presented as means ± SEM. P-values were determined by two-way ANOVA.
Extended Data Fig. 4 WEE1 is acetylated by GCN5 and deacetylated by SIRT1.
(a) SIRT1 interacts with WEE1. HEK293T cells were transfected with the indicated plasmids for 24 hr. Cell lysates were then prepared and western blot analysis was carried out as indicated. (b) SIRT1 directly interacts with WEE1 in vitro. GST-SIRT1 and MBP-WEE1 were expressed and purified from E. coli and subjected to MBP pull-down assays. (c–e) Association of endogenous SIRT1 with WEE1. Cells were irradiated with 40 J/m2 UV and allowed to recover for the indicated time. Cell lysates were then prepared and western blot analysis was carried out as indicated. (f) GCN5 acetylates WEE1 in vivo. HEK293T cells were transfected with the indicated plasmids for 24 hr. Cell lysates were then prepared and western blot analysis was carried out as indicated. (g) HEK293T cells were transfected with the indicated plasmids for 24 hr. Cell lysates were then prepared and western blot analysis was carried out as indicated. (h) WEE1 forms a complex with GCN5. HEK293T cells were transfected with the indicated plasmids for 24 hr. Cell lysates were then prepared and western blot analysis was carried out as indicated. (i) Association of endogenous WEE1 with GCN5. MDA-MB-231 cells were irradiated with 40 J/m2 UV and allowed to recover for the indicated time. Cell lysates were then prepared and western blot analysis was carried out as indicated. (j) WEE1 directly interacts with GCN5 in vitro. GST-GCN5 and MBP-WEE1 were expressed and purified from E. coli and subjected to MBP pull-down assays. (k) SIRT1 mediates WEE1 deacetylation. HEK293T cells were transfected with the indicated plasmids for 24 hr. Cell lysates were then prepared and western blot analysis was carried out as indicated. Data in A-K were independently replicated at least three times, with similar results.
Extended Data Fig. 5 WEE1 is acetylated at Lys177.
(a) The sequence of the region containing the acetylation site of WEE1 was aligned with those from various species. (b) Characterization of the anti-AcK177-WEE1 antibody by a dot blot assay. Various amounts of unacetylated or acetylated WEE1-K177 peptides were spotted onto nitrocellulose membrane and immunoblotted with the anti-AcK177-WEE1 antibody. (c) HEK293T cells were transfected with the indicated plasmids for 24 hr. Cell lysates were then prepared and western blot analysis was carried out as indicated. (d) HEK293T cells were transfected with the indicated plasmids for 24 hr. Cells were then left untreated or irradiated with 40 J/m2 UV and allowed to recover for 4 hr. Cell lysates were then prepared and western blot analysis was carried out as indicated. (e) HEK293T cells transfected with the indicated plasmids were left untreated or irradiated with 40 J/m2 UV and allowed to recover for 4 hr. Cell lysates were then prepared and western blot analysis was carried out as indicated. (f) U2OS cells were left untreated or treated with HU (4 mM), CPT (1 μM), or IR (10 Gy) for 4 hr. Cell lysates were then prepared and western blot analysis was carried out as indicated.
Extended Data Fig. 6 Acetylation is required for UV-induced CDK1 Tyr15 phosphorylation.
(a) WEE1 acetylation is required for G2/M checkpoint activation following DNA damage. A U2OS cell line to express siRNA-resistant SFB-WEE1 under the control of a tetracycline-inducible promoter was generated. The resulting cells were transfected with the indicated siRNAs and then treated with doxycycline (1 μg/mL) to induce the expression of WEE1. 8 hr later, cells were irradiated with 10 J/m2 UV and allowed to recover for 4 hr. Percentages of mitotic cells were determined by FACS analysis. Results shown are means of three independent experiments and were presented as means ± SEM. P-values were determined by two-tailed Student’s t-test. (b, c) Knockdown of GCN5 sensitizes cells to MK-1775. Results shown are means of three independent experiments and were presented as means ± SEM. P-values were determined by two-way ANOVA. (d, e) SIRT1 depletion delays mitotic entry and induces cell apoptosis. Percentages of mitotic and apoptotic cells were determined by FACS analysis. Results shown are means of three independent experiments and were presented as means ± SEM. P-values were determined by two-tailed Student’s t-test. (f) HEK293T cells were transfected with the indicated plasmids for 24 hr. Cell lysates were then prepared and western blot analysis was carried out as indicated. (g) SFB-WEE1 immunopurified from HEK293T cells were incubated with SFB-CDK1 in a kinase reaction mixture in the presence or absence of MK-1775 (10 μM). (h, i) SIRT1 sensitizes cells to MK-1775 by deacetylating WEE1. A MDA-MB-231 cell line to express siRNA-resistant SFB-WEE1 under the control of a tetracycline-inducible promoter was generated. The resulting cells were infected with lentiviruses expressing control or SIRT1 shRNAs and then transfected with the indicated siRNAs. 36 hr post-transfection, cells were treated with doxycycline (1 μg/mL for 24 hr) and indicated doses of MK-1775 for 48 hr. Results shown are means of three independent experiments and were presented as means ± SEM (I). P-values were determined by two-way ANOVA. Knockdown efficiency was confirmed by western blotting (H). Data in F-G were independently replicated at least three times, with similar results.
Extended Data Fig. 7 Acetylation at Lys177 directly activates WEE1.
(a) A schematic demonstrating the generation of site-specific acetylated recombinant WEE1 protein with an acetyl-lysine tRNA, which incorporates the acetyl-lysine on the amber codon. (b) Bacterially purified His-WEE1 or His-WEE1Lys177-Ac was incubated with SFB-CDK1 in a kinase reaction mixture. After reaction, proteins were resolved by SDS-PAGE and subjected to immunoblotting with anti-pY15-CDK1 antibody. Data in B were independently replicated at least three times, with similar results.
Extended Data Fig. 8 CHK1 promotes WEE1 phosphorylation at Ser642.
(a) U2OS cells were irradiated with 40 J/m2 UV and allowed to recover for the indicated time. (b) U2OS cells were pre-treated with CHK1 inhibitor MK-8776 (2 μM) or ATR inhibitor VE-821 (10 μM) for 1 hr prior to UV irradiation. (c) A U2OS cell line to express SFB-WEE1 under the control of a tetracycline-inducible promoter was generated. The resulting cells transfected with the indicated siRNAs were treated with doxycycline to induce the expression of WEE1. 8 hr later, cells were irradiated with 10 J/m2 UV and allowed to recover for 4 hr. Percentages of mitotic cells were determined by FACS analysis. Results shown are means of three independent experiments and were presented as means ± SEM. P-values were determined by two-tailed Student’s t-test. (d) A MDA-MB-231 cell line to express SFB-WEE1 under the control of a tetracycline-inducible promoter was generated. The resulting cells were transfected with the indicated siRNAs and then treated with doxycycline (24 hr) and indicated doses of MK-1775 for 48 hr. Results shown are means of three independent experiments and were presented as means ± SEM. P-values were determined by two-way ANOVA. (e) MDA-MB-231 cells were either synchronized in G1/S phase by a double thymidine (Thd) block or in mitosis using nocodazole (Noc) treatment. Cells were then released into the cell cycle and collected at the indicated time points. (f) MDA-MB-231 cells were synchronized in G1/S phase. Cells were then released into the cell cycle and collected at the indicated time points. (g) MDA-MB-231 cells were synchronized in G1/S phase. Cells were then treated with CHK1 inhibitor MK-8776 (2 μM), released into the cell cycle, and collected at the indicated time points. (h) MDA-MB-231 cells were either synchronized in G1/S phase or in mitosis. Cells were then released into the cell cycle and collected at the indicated time points. The co-immunoprecipitated GCN5/SIRT1 levels were normalized with immunoprecipitated WEE1 levels expressed as the normalized ratio (shown below the blots). Data in A-B, E-H were independently replicated at least three times, with similar results.
Extended Data Fig. 9 Aberrant WEE1 kinase activity induces cell apoptosis.
(a) A U2OS cell line to express siRNA-resistant SFB-WEE1 under the control of a tetracycline-inducible promoter was generated. The resulting cells were transfected with the indicated siRNAs and then treated with doxycycline (1 μg/mL) to induce the expression of WEE1. 48 hr later, percentages of apoptotic cells were determined by FACS analysis. Results shown are means of three independent experiments and were presented as means ± SEM. P-values were determined by two-tailed Student’s t-test. (b) HEK293T cells were transfected with the indicated plasmids for 24 hr. Cells were then fixed, permeabilized, and stained with anti-Flag antibody. Scale bar: 10 μm. Data in B were independently replicated at least three times, with similar results.
Extended Data Fig. 10 Acetylation relieves the inhibitory interaction between the KIM and the catalytic kinase domain.
(a) WEE1 self-associates in an intermolecular fashion. HEK293T cells transfected with the indicated plasmids were irradiated with 40 J/m2 UV and allowed to recover for 4 hr. Cell lysates were then prepared and western blot analysis was carried out as indicated. (b) WEE1 exists primarily as a dimer in non-irradiated cells. U2OS cells were irradiated with 40 J/m2 UV and allowed to recover for the indicated time. Cell lysates were then prepared and western blot analysis was carried out as indicated. (c) Mutation of Asp405 to Ala on WEE1-CK impairs its interaction with WEE1-N. Bacterially purified GST-WEE1-N or GST-WEE1-N-K177Q was incubated with amylose resin conjugated with MBP-WEE1-CK, MBP-WEE1-CK-E402A, MBP-WEE1-CK-D405A, or MBP-WEE1-CK-D426A. Proteins retained on the amylose resin were immunoblotted with anti-GST antibody. (d) Mutation of Asp405 to Ala leads to constitutive activation of WEE1. Bacterially purified MBP-WEE1-WT, MBP-WEE1-K177Q, or MBP-WEE1-D405A was incubated with SFB-CDK1 in a kinase reaction mixture. After reaction, proteins were resolved by SDS-PAGE and subjected to immunoblotting. (e) Bacterially purified MBP-WEE1-N, MBP-WEE1-N-K177R, or MBP-WEE1-N-K177Q was mixed with SFB-WEE1 immunopurified from HEK293T cells that were left untreated or irradiated with 40 J/m2 UV and allowed to recover for 4 hr in a kinase reaction buffer. The mixture was then incubated with SFB-CDK1 in the presence of 0.3 mM ATP. After reaction, proteins were resolved by SDS-PAGE and subjected to immunoblotting. (f) Bacterially purified MBP-WEE1-N, MBP-WEE1-N-K177R, or MBP-WEE1-N-K177Q was mixed with MBP-WEE1-CK in a kinase reaction buffer. The mixture was then incubated with SFB-CDK1 in the presence of 0.3 mM ATP. After reaction, proteins were resolved by SDS-PAGE and subjected to immunoblotting. Data in A-F were independently replicated at least three times, with similar results.
Supplementary information
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Zhu, X., Su, Q., Xie, H. et al. SIRT1 deacetylates WEE1 and sensitizes cancer cells to WEE1 inhibition. Nat Chem Biol 19, 585–595 (2023). https://doi.org/10.1038/s41589-022-01240-y
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DOI: https://doi.org/10.1038/s41589-022-01240-y
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