Activation of the CCL22/CCR4 causing EMT process remodeling under EZH2-mediated epigenetic regulation in cervical carcinoma

• Published in: Journal of Cancer 2024, Vol.15 (19), p.6299-6314
• Main Authors: Zhang, Li, Tian, Sijuan, Chang, Jie, Quan, Shimin, Yang, Ting, Zhao, Minyi, Wang, Li, Yang, Xiaofeng
• Format: Article
• Language: English
• Subjects: Research Paper
• ISSN: 1837-9664; 1837-9664
• DOI: 10.7150/jca.101881

Cervical cancer (CC) is an important public health problem for women, gene expression patterns which were governed by epigenetic modifications can result in CC, CC-chemokine receptor 4 (CCR4) interacts with C-C-motif ligand 22 (CCL22) is associated with tumor progression or metastasis. A previous study by the present authors revealed the levels of chemokine CCL22 and its receptor CCR4 are increased in CC tissues, nevertheless, the regulatory mechanisms governing its expression remain poorly understood. The present study aimed to investigate the potential role of enhancer of zeste homolog 2 (EZH2)-induced epigenetic activation of CCL22/CCR4 and caused epithelial-to-mesenchymal transition (EMT) remodeling in CC. CCL22 and CCR4 were significantly up-regulated in CC samples compared with normal cervix tissues, and obvious induction of promoter DNA methylation levels of and was found in CC tissues. Demethylation reactivated the transcription of and . DNA methyltransferase 3A (DNMT3A) was found to directly bind to the and promoter regions . Downregulation of the expression of EZH2 in CC cell lines altered DNMT3A expression and induced and promoters' methylation levels, while and mRNA expression decreased. An assay showed that EZH2 regulated the expression of CCL22/CCR4 components through DNMT3A, consistent with the results. In EZH2-silenced CC cells, migration was reduced, levels of EMT-related markers, including vimentin, slug, snail and β-catenin, were all reduced and zona occludens 1 (ZO-1) increased. In DNMT3A-silenced CC cells, migration was induced, vimentin, slug, snail and β-catenin were all induced and ZO-1 was reduced. Inhibition of CCL22 protein significantly decreased migration of CC cells and vimentin, slug, snail and β-catenin levels, while ZO-1 increased. In conclusion, EZH2 appears to regulate CCL22/CCR4 expression via epigenetic activation, causing EMT process remodeling in CC progression.