FOXA1 Targets NEK2 to Mediate Cisplatin Resistance in Lung Adenocarcinoma Cells by Activating DNA Damage Repair

Abstract

Lung adenocarcinoma (LUAD) is one of the main causes of death in cancer patients, as its hidden course is difficult to uncover, resulting in many patients being diagnosed as advanced. Late-stage LUAD patients are prone to develop resistance to cisplatin. This study aims to explore the potential molecular regulatory mechanism of NEK2 on cisplatin resistance in LUAD cells. The expression levels of NEK2 and FOXA1 in LUAD tissues were analyzed based on bioinformatics methods. qRT-PCR analysis was carried out to measure the mRNA expression levels of NEK2 and FOXA1 in LUAD cells. CCK8 detected and calculated cell viability and IC₅₀ values for each group of cells. Gene set enrichment analysis (GSEA) analyzed signaling pathways enriched by the NEK2 gene in LUAD. Dual luciferase and CHIP experiments were conducted to verify the binding relationship between NEK2 and FOXA1. Comet assay was utilized to analyze the level of DNA damage in LUAD cells. Western blot (WB) measured the expression levels of DNA damage-related proteins (γ-H2AX, p-ATM). The experimental results showed that FOXA1 and NEK2 were highly expressed in LUAD tissues and cells. GSEA analysis showed that NEK2 was enriched in DNA damage-related pathways, and silencing NEK2 could reduce the vitality of LUAD cisplatin-resistant cells, lower the IC₅₀ value of cells to cisplatin, and increase their DNA damage levels. FOXA1 can target the promoter region that binds to NEK2, and it can activate NEK2 through transcription to promote DNA damage repair and cisplatin resistance in cisplatin-resistant LUAD cells. This study confirms that FOXA1 can target NEK2 to promote DNA damage repair and cisplatin resistance in LUAD cells, providing a new valuable therapeutic target for the treatment of LUAD and the control of chemotherapy drug resistance.