Kdm4a, a histone lysine-specific demethylase, belongs to the Fe-II dependent dioxygenase family. It uses α-ketoglutarate and molecular oxygen as cofactors and demethylates lysine 9 (H3K9me2/3) and lysine 36 (H3K36me3) methyl marks on histone H3. This enzymatic activity is involved in regulating gene expression, cellular differentiation, and is crucial for various biological processes such as myogenesis, memory formation, and also has implications in tumor-related pathways [2,3,6]. Genetic models, like KO/CKO mouse models, are valuable tools to study its functions.

In squamous cell carcinoma (SCC), inhibition of Kdm4a promotes heterochromatin compaction and DNA replication stress, which activates tumor-cell-intrinsic cGAS-STING signaling, leading to antitumor immunity. Moreover, it collaborates with PD1 blockade to inhibit SCC growth and metastasis by recruiting and activating CD8+ T cells and eliminating cancer stem cells [1]. In bladder cancer, ML324, a Kdm4a inhibitor, downregulates Sqle transcription by blocking the demethylation-mediated chromatin opening for Gabpa access to the Sqle promoter. This leads to cholesterol synthesis blockade, squalene accumulation, ROS-related apoptosis, and tumor growth inhibition [4]. In osteosarcoma, Kdm4a knockdown promotes ferroptosis, a non-apoptotic cell death, by regulating SLC7A11 transcription through H3K9me3 demethylation in its promoter region, inhibiting tumor progression and lung metastasis [5].

In conclusion, Kdm4a is a key regulator in multiple biological processes. Through KO/CKO mouse models and other loss-of-function experiments, its role in tumor-related diseases like SCC, bladder cancer, and osteosarcoma has been revealed. Understanding Kdm4a's functions provides potential therapeutic targets for these diseases.