KLF5 Promotes Esophageal Squamous Cell Carcinoma Radioresistance by Targeting the Keap1-Nrf2 Pathway

Overview

Journal Discov Oncol

Publisher Springer

Date 2025 Feb 7

PMID 39918680

Authors

Yang Wang

Yue-Ying Yang

Abulajiang Kamili

Dilimulati Aishanjiang

Yi Liu

Affiliations

Soon will be listed here.

Abstract

Objective: Esophageal squamous cell carcinoma (ESCC) has high morbidity and mortality in developing countries. The purpose of this article is to study the mechanism of KLF5's effect on ESCC radiosensitivity.

Methods: WGCNA gene expression profiling identified core genes associated with ESCC radiosensitivity. KLF5 expression was detected by RT-qPCR. The effects of overexpression or downregulation of KLF5 on anti-irradiated cells' proliferation, migration, invasion, and apoptotic activity were studied through colony formation assay, Transwell assay, and flow cytometry. Western blot can detect the activity of Nrf2 signaling pathway in cells and tissues. The enrichment of KLF5 at the Keap1 promoter was analyzed by ChIP-base, and the binding of KLF5 to Keap1 was analyzed by ChIP and dual-luciferase. They then injected ESCC cells into mice and used radiation to monitor tumor progression.

Results: KLF5 is a core gene in ESCC and is significantly associated with radiosensitivity. KLF5 expression is upregulated in drug-resistant ESCC cells. Overexpression of KLF5 significantly increased cell viability and attenuated cellular responses to radiation. KLF5 knockdown reduces radioresistance. After KLF5 overexpression, the Nrf2 signaling pathway was significantly up-regulated, and after KLF5 was up-regulated, the Keap1 signaling pathway was down-regulated. KLF5 inhibits the transcriptional activity of Keap1. Upregulation of Keap1 inhibits the effect of KLF5 overexpression on radioresistance of ESCC cells. KLF5/Keap1 regulates the effects of ESCC on in vivo radiotherapy.

Conclusion: KLF5 promotes ESCC radioresistance by inhibiting Keap1 transcription and activating the Nrf2 pathway.

References

Wang F, Luo M, Qu H, Cheng Y . BAP1 promotes viability and migration of ECA109 cells through KLF5/CyclinD1/FGF-BP1. FEBS Open Bio. 2021; 11(5):1497-1503. PMC: 8091813. DOI: 10.1002/2211-5463.13105. View

Jiang Y, Jiang Y, Li C, Zhang Y, Dakle P, Kaur H . TP63, SOX2, and KLF5 Establish a Core Regulatory Circuitry That Controls Epigenetic and Transcription Patterns in Esophageal Squamous Cell Carcinoma Cell Lines. Gastroenterology. 2020; 159(4):1311-1327.e19. DOI: 10.1053/j.gastro.2020.06.050. View

Li M, Fan L, Han D, Yu Z, Ma J, Liu Y . Ribosomal S6 protein kinase 4 promotes radioresistance in esophageal squamous cell carcinoma. J Clin Invest. 2020; 130(8):4301-4319. PMC: 7410060. DOI: 10.1172/JCI134930. View

Huang D, Gao Q, Guo L, Zhang C, Jiang W, Li H . Isolation and identification of cancer stem-like cells in esophageal carcinoma cell lines. Stem Cells Dev. 2008; 18(3):465-73. DOI: 10.1089/scd.2008.0033. View

Sun X, Sun Y, Li J, Zhao X, Shi X, Gong T . SOCS6 promotes radiosensitivity and decreases cancer cell stemness in esophageal squamous cell carcinoma by regulating c-Kit ubiquitylation. Cancer Cell Int. 2021; 21(1):165. PMC: 7953756. DOI: 10.1186/s12935-021-01859-2. View

Feng L, Zhao K, Sun L, Yin X, Zhang J, Liu C . SLC7A11 regulated by NRF2 modulates esophageal squamous cell carcinoma radiosensitivity by inhibiting ferroptosis. J Transl Med. 2021; 19(1):367. PMC: 8393811. DOI: 10.1186/s12967-021-03042-7. View

Waters J, Reznik S . Update on Management of Squamous Cell Esophageal Cancer. Curr Oncol Rep. 2022; 24(3):375-385. DOI: 10.1007/s11912-021-01153-4. View

Jurkovicova D, Neophytou C, cipak Gasparovic A, Goncalves A . DNA Damage Response in Cancer Therapy and Resistance: Challenges and Opportunities. Int J Mol Sci. 2022; 23(23). PMC: 9735783. DOI: 10.3390/ijms232314672. View

Xia D, Zhang X, Ma Y, Zhao Z, Zhao R, Wang Y . Nrf2 promotes esophageal squamous cell carcinoma (ESCC) resistance to radiotherapy through the CaMKIIα-associated activation of autophagy. Cell Biosci. 2020; 10:90. PMC: 7392680. DOI: 10.1186/s13578-020-00456-6. View

10.

Dai H, Wei Y, Liu Y, Liu J, Yu R, Zhang J . Pathway-Based Analysis Revealed the Role of Keap1-Nrf2 Pathway and PI3K-Akt Pathway in Chinese Esophageal Squamous Cell Carcinoma Patients With Definitive Chemoradiotherapy. Front Genet. 2022; 12:799663. PMC: 9081370. DOI: 10.3389/fgene.2021.799663. View

11.

Reichenbach Z, Murray M, Saxena R, Farkas D, Karassik E, Klochkova A . Clinical and translational advances in esophageal squamous cell carcinoma. Adv Cancer Res. 2019; 144:95-135. DOI: 10.1016/bs.acr.2019.05.004. View

12.

Xia Y, Fang Y, Zhang H, Shen C, Wang P, Yan W . Role of Kruppel-Like Factor 5 in Deoxycholic Acid-Mediated Intestinal Transdifferentiation of Esophageal Squamous Epithelium. J Cancer. 2019; 10(22):5597-5607. PMC: 6775683. DOI: 10.7150/jca.30050. View

13.

Lee N, Chan C, Tung L, Wang H, Law S . Tumor xenograft animal models for esophageal squamous cell carcinoma. J Biomed Sci. 2018; 25(1):66. PMC: 6116446. DOI: 10.1186/s12929-018-0468-7. View

14.

Zhang J, Jiao Q, Kong L, Yu J, Fang A, Li M . Nrf2 and Keap1 abnormalities in esophageal squamous cell carcinoma and association with the effect of chemoradiotherapy. Thorac Cancer. 2018; 9(6):726-735. PMC: 5983206. DOI: 10.1111/1759-7714.12640. View

15.

Wang Z, Zhang J, Li M, Kong L, Yu J . The expression of p-p62 and nuclear Nrf2 in esophageal squamous cell carcinoma and association with radioresistance. Thorac Cancer. 2019; 11(1):130-139. PMC: 6938765. DOI: 10.1111/1759-7714.13252. View

16.

Wang R, Liu S, Chen B, Xi M . Recent Advances in Combination of Immunotherapy and Chemoradiotherapy for Locally Advanced Esophageal Squamous Cell Carcinoma. Cancers (Basel). 2022; 14(20). PMC: 9599968. DOI: 10.3390/cancers14205168. View

17.

Furfaro A, Traverso N, Domenicotti C, Piras S, Moretta L, Marinari U . The Nrf2/HO-1 Axis in Cancer Cell Growth and Chemoresistance. Oxid Med Cell Longev. 2015; 2016:1958174. PMC: 4677237. DOI: 10.1155/2016/1958174. View

18.

Wu Z, Zhou J, Zhang X, Zhang Z, Xie Y, Liu J . Reprogramming of the esophageal squamous carcinoma epigenome by SOX2 promotes ADAR1 dependence. Nat Genet. 2021; 53(6):881-894. PMC: 9124436. DOI: 10.1038/s41588-021-00859-2. View

19.

Hirose W, Oshikiri H, Taguchi K, Yamamoto M . The KEAP1-NRF2 System and Esophageal Cancer. Cancers (Basel). 2022; 14(19). PMC: 9564177. DOI: 10.3390/cancers14194702. View

20.

Fabrizio F, Sparaneo A, Trombetta D, Muscarella L . Epigenetic versus Genetic Deregulation of the KEAP1/NRF2 Axis in Solid Tumors: Focus on Methylation and Noncoding RNAs. Oxid Med Cell Longev. 2018; 2018:2492063. PMC: 5872633. DOI: 10.1155/2018/2492063. View