KDM2A demethylase: A versatile epigenetic regulator in development, cancer, and therapeutic horizons.

Lysine demethylase 2A (KDM2A), a crucial member of the histone demethylase family, plays a vital role in epigenetic regulation by modifying histone methylation and the chromatin structure. It regulates key cellular activities, including development, differentiation, and metabolism, by controlling gene expression and transcriptional silencing, and maintaining genomic stability through the demethylation of histone H3 at lysine 36 (H3K36). In addition to its canonical enzymatic role, KDM2A is involved in diverse biological processes, together with embryonic development, stem cell maintenance, DNA damage response, and metabolic homeostasis. Throughout development, it facilitates gene silencing and activation by engaging DNA regions rich in cytosine-guanine (CpG) dinucleotides and attracting polycomb repressive complexes (PRC), which affect lineage specification and organogenesis. Here, we outline the disease-related effects of KDM2A dysregulation related to developmental disorders, cancers, and metastasis. KDM2A aids in tumor development by influencing cell cycle regulators, oncogenes, and chromatin accessibility while also being involved in preserving cancer stem cell characteristics and facilitating epithelial-mesenchymal transition (EMT), metabolic reprogramming, and interactions with cancer-associated fibroblasts (CAFs). Its dual function as an oncogene and tumor suppressor, which varies with the cellular context, highlights its drug complexity and resistance. This review discusses the multifaceted epigenetic functions of KDM2A under both normal and diseased conditions, emphasizing its increasing importance as a potential epigenetic target. It also summarizes the progress in KDM2A-targeted therapies, including inhibitors, RNA interference, CRISPR-Cas9, and immunoepigenetic strategies, with a focus on future applications of KDM2A modulation in clinical treatments for cancer and other epigenetic-associated diseases.