KDM1A Facilitates Oncogenic Potential in Colorectal Cancer Progression Through the Activation of AXIN/GSK3β/β‐Catenin Signaling Pathways: Evidence From Integrated Transcriptomics and In Vitro Studies

BACKGROUND: Colorectal cancer (CRC) is a major cause of cancer-related death and is driven by epigenetic alterations. KDM1A, a key histone demethylase, has a poorly defined role in CRC. This study investigates its molecular mechanisms using bioinformatic and experimental analyses to better understand its impact on tumor progression. METHODS: KDM1A expression was analyzed using TCGA datasets to assess its correlation with CRC progression and patient survival. CRC cell lines were treated with the KDM1A-specific inhibitor GSK2879552, both alone and in combination with 5-Aza and XAV939. Functional assays, including cell proliferation, cell cycle analysis, ROS measurement, glycolysis assessment, and G6PD activity, were performed to evaluate the effects of KDM1A inhibition. Protein and gene expression were examined by Western blotting and RT-PCR analysis. RESULTS: KDM1A expression was significantly upregulated in advanced CRC and was associated with poor survival. Treatment with GSK2879552 inhibited CRC cell proliferation, induced G1-phase arrest, reduced aerobic glycolysis, and increased ROS levels. Combination with 5-Aza and XAV939 further enhanced the antitumor effects, demonstrating synergistic potential in CRC cells. CONCLUSIONS: KDM1A regulates CRC progression by modulating epithelial-mesenchymal transition (EMT), metabolism, and Wnt signaling. Targeting KDM1A with GSK2879552 represents a promising therapeutic strategy for CRC treatment.