Natural product mediated mesenchymal-epithelial remodeling by covalently binding ENO1 to degrade m6A modified β-catenin mRNA.
10.1016/j.apsb.2024.07.013
- Author:
Tianyang CHEN
1
;
Guangju LIU
1
;
Sisi CHEN
1
;
Fengyuan ZHANG
1
;
Shuoqian MA
1
;
Yongping BAI
1
;
Quan ZHANG
1
;
Yahui DING
2
Author Information
1. State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300353, China.
2. College of Chemistry, Nankai University, Tianjin 300071, China.
- Publication Type:Journal Article
- Keywords:
ENO1;
Mesenchymal‒epithelial remodeling;
Natural product;
Target identification;
β-Catenin
- From:
Acta Pharmaceutica Sinica B
2025;15(1):467-483
- CountryChina
- Language:English
-
Abstract:
The transition of cancer cells from epithelial state to mesenchymal state awarded hepatocellular carcinoma (HCC) stem cell properties and induced tumorigenicity, drug resistance, and high recurrence rate. Reversing the mesenchymal state to epithelial state by inducing mesenchymal-epithelial remodeling could inhibit the progression of HCC. Using high-throughput screening, chrysin was selected from natural products to reverse epithelial-mesenchymal transition (EMT) by selectively increasing CDH1 expression. The target identification suggested chrysin exerted its anti-HCC effect through covalently and specifically binding threonine 205 (Thr205) of alpha-enolase (ENO1). For the first time, we revealed that ENO1 bound β-catenin mRNA, and recruited YTHDF2 to identify the m6A modified β-catenin in the 3'-UTR region to degrade β-catenin mRNA. Eventually, the CDH1 gene expression was improved through the regulation of β-catenin mRNA. ENO1/β-catenin mRNA interaction might be a promising target for cellular plasticity reprogramming. Moreover, chrysin could mediate mesenchymal‒epithelial remodeling through increasing degradation of β-catenin mRNA by promoting the binding of ENO1 and β-catenin mRNA. To the best of our knowledge, chrysin is the first reported small molecule inducing β-catenin mRNA degradation through binding to ENO1. The water-soluble derivative of chrysin may be a natural product-derived lead compound for circumventing metastasis, recurrence, and drug resistance of HCC by mediating mesenchymal‒epithelial remodeling.
