Activation of the CCL22/CCR4 Causing EMT Process Remodeling Under EZH2-mediated Epigenetic Regulation in Cervical Carcinoma

Overview

Journal J Cancer

Specialty Oncology

Date 2024 Nov 8

PMID 39513112

Authors

Li Zhang

Sijuan Tian

Jie Chang

Shimin Quan

Ting Yang

Minyi Zhao

Li Wang

Xiaofeng Yang

Affiliations

Soon will be listed here.

Abstract

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.

References

Madsen A, Hoppner G, Krause J, Hirt M, Laufer S, Schweizer M . An Important Role for DNMT3A-Mediated DNA Methylation in Cardiomyocyte Metabolism and Contractility. Circulation. 2020; 142(16):1562-1578. PMC: 7566310. DOI: 10.1161/CIRCULATIONAHA.119.044444. View

Law J, Jacobsen S . Establishing, maintaining and modifying DNA methylation patterns in plants and animals. Nat Rev Genet. 2010; 11(3):204-20. PMC: 3034103. DOI: 10.1038/nrg2719. View

Wagsater D, Dienus O, Lofgren S, Hugander A, Dimberg J . Quantification of the chemokines CCL17 and CCL22 in human colorectal adenocarcinomas. Mol Med Rep. 2011; 1(2):211-7. View

Wang Q, Schmoeckel E, Kost B, Kuhn C, Vattai A, Vilsmaier T . Higher CCL22+ Cell Infiltration is Associated with Poor Prognosis in Cervical Cancer Patients. Cancers (Basel). 2019; 11(12). PMC: 6966573. DOI: 10.3390/cancers11122004. View

Bogacka J, Pawlik K, Ciapala K, Ciechanowska A, Mika J . CC Chemokine Receptor 4 (CCR4) as a Possible New Target for Therapy. Int J Mol Sci. 2022; 23(24). PMC: 9779674. DOI: 10.3390/ijms232415638. View

Steenbergen R, Snijders P, Heideman D, Meijer C . Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions. Nat Rev Cancer. 2014; 14(6):395-405. DOI: 10.1038/nrc3728. View

Liu H, Ma H, Li Y, Zhao H . Advances in epigenetic modifications and cervical cancer research. Biochim Biophys Acta Rev Cancer. 2023; 1878(3):188894. DOI: 10.1016/j.bbcan.2023.188894. View

Papanicolau-Sengos A, Aldape K . DNA Methylation Profiling: An Emerging Paradigm for Cancer Diagnosis. Annu Rev Pathol. 2021; 17:295-321. DOI: 10.1146/annurev-pathol-042220-022304. View

Scheu S, Ali S, Ruland C, Arolt V, Alferink J . The C-C Chemokines CCL17 and CCL22 and Their Receptor CCR4 in CNS Autoimmunity. Int J Mol Sci. 2017; 18(11). PMC: 5713275. DOI: 10.3390/ijms18112306. View

10.

Tsujikawa T, Yaguchi T, Ohmura G, Ohta S, Kobayashi A, Kawamura N . Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma. Int J Cancer. 2012; 132(12):2755-66. DOI: 10.1002/ijc.27966. View

11.

Lyko F . The DNA methyltransferase family: a versatile toolkit for epigenetic regulation. Nat Rev Genet. 2017; 19(2):81-92. DOI: 10.1038/nrg.2017.80. View

12.

Yoshie O . CCR4 as a Therapeutic Target for Cancer Immunotherapy. Cancers (Basel). 2021; 13(21). PMC: 8583476. DOI: 10.3390/cancers13215542. View

13.

Yamagishi M, Uchimaru K . Targeting EZH2 in cancer therapy. Curr Opin Oncol. 2017; 29(5):375-381. DOI: 10.1097/CCO.0000000000000390. View

14.

Liu Y, Yang Q . The roles of EZH2 in cancer and its inhibitors. Med Oncol. 2023; 40(6):167. PMC: 10162908. DOI: 10.1007/s12032-023-02025-6. View

15.

Jiang M, Fang X, Ma L, Liu M, Chen M, Liu J . A nucleus-targeting peptide antagonist towards EZH2 displays therapeutic efficacy for lung cancer. Int J Pharm. 2022; 622:121894. DOI: 10.1016/j.ijpharm.2022.121894. View

16.

Hao Y, Baker D, Ten Dijke P . TGF-β-Mediated Epithelial-Mesenchymal Transition and Cancer Metastasis. Int J Mol Sci. 2019; 20(11). PMC: 6600375. DOI: 10.3390/ijms20112767. View

17.

Cao L, Hu X, Zhang J, Huang G, Zhang Y . The role of the CCL22-CCR4 axis in the metastasis of gastric cancer cells into omental milky spots. J Transl Med. 2014; 12:267. PMC: 4177767. DOI: 10.1186/s12967-014-0267-1. View

18.

Zhang L, Tian S, Zhao M, Yang T, Quan S, Yang Q . SUV39H1-DNMT3A-mediated epigenetic regulation of Tim-3 and galectin-9 in the cervical cancer. Cancer Cell Int. 2020; 20:325. PMC: 7370487. DOI: 10.1186/s12935-020-01380-y. View

19.

Huang Y, Chang C, Kuo Y, Fang W, Kao H, Tsai S . Cancer-associated fibroblast-derived interleukin-1β activates protumor C-C motif chemokine ligand 22 signaling in head and neck cancer. Cancer Sci. 2019; 110(9):2783-2793. PMC: 6726685. DOI: 10.1111/cas.14135. View

20.

Ma Q, Zhao M, Wei X, Zhao J, Yang T, Zhang Q . Expressions of Immune Negative Regulator FoxP3+Treg and PD-L1 Protein in the Immune Microenvironment of Cervical Lesion. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2017; 39(1):128-132. DOI: 10.3881/j.issn.1000-503X.2017.01.021. View