Diverse Functions of KDM5 in Cancer: Transcriptional Repressor or Activator?

SIMPLE SUMMARY: Aberrations in epigenetic modulators have been widely identified in cancer; therefore, these modulators are attractive targets for cancer treatment. KDM5 is an H3K4 demethylase family that is recognized as a cancer-associated epigenetic regulator. However, the role of KDM5 and its transcriptional regulation in cancer is multifaceted. Here, we provide an overview of the roles of KDM5 in cancer, explore the molecular mechanisms through which KDM5 regulates transcriptional output, including our recent finding that KDM5A supports transcriptional activation by controlling the H3K4 methylation cycle, and further discuss the possibility of the use of KDM5 inhibitors in cancer therapy. ABSTRACT: Epigenetic modifications are crucial for chromatin remodeling and transcriptional regulation. Post-translational modifications of histones are epigenetic processes that are fine-tuned by writer and eraser enzymes, and the disorganization of these enzymes alters the cellular state, resulting in human diseases. The KDM5 family is an enzymatic family that removes di- and tri-methyl groups (me2 and me3) from lysine 4 of histone H3 (H3K4), and its dysregulation has been implicated in cancer. Although H3K4me3 is an active chromatin marker, KDM5 proteins serve as not only transcriptional repressors but also transcriptional activators in a demethylase-dependent or -independent manner in different contexts. Notably, KDM5 proteins regulate the H3K4 methylation cycle required for active transcription. Here, we review the recent findings regarding the mechanisms of transcriptional regulation mediated by KDM5 in various contexts, with a focus on cancer, and further shed light on the potential of targeting KDM5 for cancer therapy.