Post-translational modification of CDK1-STAT3 signaling by fisetin suppresses pancreatic cancer stem cell properties

Xiaodong Xu; Yimin Ding; Junbin Jin; Chengjie Xu; Wenyi Hu; Songtao Wu; Guoping Ding; Rui Cheng; Liping Cao; Shengnan Jia

doi:10.1186/s13578-023-01118-z

Post-translational modification of CDK1-STAT3 signaling by fisetin suppresses pancreatic cancer stem cell properties

Cell Biosci. 2023 Sep 24;13(1):176. doi: 10.1186/s13578-023-01118-z.

Authors

Xiaodong Xu^#^{1

2}, Yimin Ding^#¹, Junbin Jin¹, Chengjie Xu¹, Wenyi Hu¹, Songtao Wu¹, Guoping Ding¹, Rui Cheng³, Liping Cao^{4

5}, Shengnan Jia^{6

7}

Affiliations

¹ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China.
² General Surgery, Cancer Center, Department of Colorectal Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, 310014, Zhejiang, China.
³ State Key Laboratory of Food Science and Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122, China.
⁴ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China. caolipingzju@zju.edu.cn.
⁵ Innovation Center for Minimally Invasive Technique and Device, Zhejiang University, Hangzhou, 310000, Zhejiang, China. caolipingzju@zju.edu.cn.
⁶ Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310000, China. jiashengnan8180@zju.edu.cn.
⁷ Innovation Center for Minimally Invasive Technique and Device, Zhejiang University, Hangzhou, 310000, Zhejiang, China. jiashengnan8180@zju.edu.cn.

^# Contributed equally.

Abstract

Background: 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.

Results: 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.

Conclusion: 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.

Keywords: CDK1; Cancer stem cells; Fisetin; Pancreatic ductal adenocarcinoma; STAT3.

Abstract

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