SIRT1 deacetylates WEE1 and sensitizes cancer cells to WEE1 inhibition
SIRT1 deacetylates WEE1 and sensitizes cancer cells to WEE1 inhibition
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DOI：
10.1038/s41589-022-01240-y
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发表时间：
2023-01
影响因子：
14.8
通讯作者：
Xiaomei Zhu;Qunshu Su;Haiyuan Xie;Lizhi Song;Fan Yang;Dandan Zhang;Binghong Wang;Shixian Lin;Jun Huang;Mengjie Wu;Ting Liu
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文献类型：
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作者：
Xiaomei Zhu;Qunshu Su;Haiyuan Xie;Lizhi Song;Fan Yang;Dandan Zhang;Binghong Wang;Shixian Lin;Jun Huang;Mengjie Wu;Ting Liu
细胞周期检查点激酶WEE1正在成为癌症治疗的治疗靶点。然而，其催化活性如何调节仍然知之甚少，预测对WEE 1抑制剂反应的可靠生物标志物仍有待鉴定。在这里，我们确定了一个进化保守的片段周围的Lys177残基，抑制WEE1活性，通过与催化激酶结构域的分子间相互作用。在DNA损伤后，CHK1依赖的WEE1在Ser642的磷酸化引发GCN 5介导的Lys177的乙酰化，导致抑制性片段从激酶结构域解离，随后激活WEE1和细胞周期检查点。相反，SIRT 1与WEE 1结合并使其脱乙酰化，从而使其保持在非活性状态。因此，SIRT 1缺陷诱导WEE 1过度乙酰化和活化，使癌细胞对WEE 1抑制产生抗性。这些结果表明，肿瘤细胞中SIRT 1表达水平和WEE 1 Lys177乙酰化丰度可作为预测WEE 1抑制剂敏感性或耐药性的有用生物标志物。
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.