Post-translational modification of CDK1-STAT3 signaling by fisetin suppresses pancreatic cancer stem cell properties.
Post-translational modification of CDK1-STAT3 signaling by fisetin suppresses pancreatic cancer stem cell properties.
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DOI：
10.1186/s13578-023-01118-z
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发表时间：
2023-09-24
影响因子：
7.5
通讯作者：
Jia, Shengnan
中科院分区：
文献类型：
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作者：
Xu, Xiaodong;Ding, Yimin;Jin, Junbin;Xu, Chengjie;Hu, Wenyi;Wu, Songtao;Ding, Guoping;Cheng, Rui;Cao, Liping;Jia, Shengnan
胰腺癌干细胞（CSC）促进胰腺导管腺癌（PDAC）肿瘤发生和化学抗性。细胞周期蛋白依赖性激酶1（Cyclin-dependent kinase 1，CDK 1）在其他肿瘤的发生中起重要作用，但CDK 1在PDAC中的作用尚不清楚。非瑟酮是一种生物活性类黄酮，在多种肿瘤中具有抗肿瘤特性，但其在CSC中的功能仍然难以捉摸。在这项研究中，我们证明了CDK 1与预后相关，并且在胰腺癌组织和吉西他滨耐药细胞中高度表达。沉默CDK 1削弱了肿瘤的干细胞性并减少了CSC的亚群。我们发现非瑟酮阻断了CDK 1的激酶口袋结构域，并抑制了胰腺CSC的特性。利用乙酰化蛋白质组学分析和磷酸化阵列分析，我们证实非瑟酮降低CDK 1的表达，并增加CDK 1在赖氨酸33（K33）的乙酰化，从而导致抑制CDK 1的磷酸化。沉默CDK 1或STAT 3抑制肿瘤干细胞特性，而过表达CDK 1或STAT 3显示相反的效果。CDK 1在K33的突变或乙酰化减弱了STAT 3在Y 705的磷酸化，损害了干细胞相关基因的表达和胰腺癌的干细胞性。此外，缺乏组蛋白去乙酰化酶3（HDAC 3），使CDK 1去乙酰化，有助于通过调节CDK 1的翻译后修饰来削弱STAT 3磷酸化，从而降低PDAC的干性。此外，我们的研究结果表明，非瑟酮增强吉西他滨的效果，通过消除胰腺CSC的亚群，通过抑制CDK 1-STAT 3轴在体外和体内。我们的研究结果强调了CDK 1-STAT 3信号转导的翻译后修饰在维持PDAC的癌症干性中的作用，并表明用抑制剂如非瑟酮靶向CDK 1-STAT 3轴是一种潜在的治疗策略，可以减少耐药性并消除PDAC。在线版本包含补充材料，可通过10.1186/s13578-023-01118-z获得。
Pancreatic cancer stem cells (CSCs) promote pancreatic ductal adenocarcinoma (PDAC) tumorigenesis and chemoresistance. Cyclin-dependent kinase 1 (CDK1) plays an important role in tumor initiation in other tumors, but the function of CDK1 in PDAC remains unclear. Fisetin is a bioactive flavonoid with anti-tumor properties in multiple tumors, while its function in CSCs remains elusive. In this study, we demonstrated that CDK1 was correlated with prognosis and was highly expressed in pancreatic cancer tissue and gemcitabine-resistant cells. Silencing CDK1 impaired tumor stemness and reduced a subset of CSCs. We found that fisetin blocked the kinase pocket domain of CDK1 and inhibited pancreatic CSC characteristics. Using acetylation proteomics analysis and phosphorylation array assay, we confirmed that fisetin reduced CDK1 expression and increased CDK1 acetylation at lysine 33 (K33), which resulted in the suppression of CDK1 phosphorylation. Silencing CDK1 or STAT3 suppressed tumor stemness properties, while overexpressing CDK1 or STAT3 showed the opposite effect. Mutation or acetylation of CDK1 at K33 weakened STAT3 phosphorylation at Y705, impairing the expression of stem-related genes and pancreatic cancer stemness. In addition, lack of histone deacetylase 3 (HDAC3), which deacetylates CDK1, contributed to weakening STAT3 phosphorylation by regulating the post-translational modification of CDK1, thereby decreasing the stemness of PDAC. Moreover, our results revealed that fisetin enhanced the effect of gemcitabine through eliminating a subpopulation of pancreatic CSCs by inhibiting the CDK1–STAT3 axis in vitro and in vivo. Our findings highlight the role of post-translational modifications of CDK1–STAT3 signaling in maintaining cancer stemness of PDAC, and indicated that targeting the CDK1–STAT3 axis with inhibitors such as fisetin is a potential therapeutic strategy to diminish drug resistance and eliminate PDAC. The online version contains supplementary material available at 10.1186/s13578-023-01118-z.
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影响因子：
14.9
作者：
Mateo F;Vidal-Laliena M;Canela N;Zecchin A;Martínez-Balbás M;Agell N;Giacca M;Pujol MJ;Bachs O
通讯作者：
Bachs O
组蛋白脱乙酰酶 3 通过信号转导器和转录 3 信号通路激活剂促进肝脏再生和肝癌细胞增殖。
影响因子：
9
作者：
Lu XF;Cao XY;Zhu YJ;Wu ZR;Zhuang X;Shao MY;Xu Q;Zhou YJ;Ji HJ;Lu QR;Shi YJ;Zeng Y;Bu H
通讯作者：
Bu H
DOI：
10.1016/j.bbrc.2014.03.118
发表时间：
2014-04-25
影响因子：
3.1
作者：
Lee, Juhyung;Yun, Nuri;Oh, Young J.
通讯作者：
Oh, Young J.
影响因子：
29.4
作者：
Dandawate, Prasad;Kaushik, Gaurav;Anant, Shrikant
通讯作者：
Anant, Shrikant
影响因子：
11.4
作者：
通讯作者：
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