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

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.

Broad H3K4me3 domains: Maintaining cellular identity and their implication in super‐enhancer hijacking

“…[ 43 ] The KDM5 family of H3K4 demethylases (reviewed in ref. [44]) have been shown to repress transcription but also activate transcription in a demethylase‐dependent and independent manner. [ 44 ] KDM5A/B/C and D have all been implicated in cancer, for example, KDM5B was first identified in breast cancer where tumour suppressor genes (TSGs) are repressed by its activity, thus promoting proliferation.…”

“…[44]) have been shown to repress transcription but also activate transcription in a demethylase‐dependent and independent manner. [ 44 ] KDM5A/B/C and D have all been implicated in cancer, for example, KDM5B was first identified in breast cancer where tumour suppressor genes (TSGs) are repressed by its activity, thus promoting proliferation. [ 45 ] Removal of acetylation is performed by histone deacetylases (HDACs) such as HDAC1/2/3 which disrupts core regulatory TF binding, thus silencing promoters or enhancers.…”

Drawing a line between histone demethylase KDM5A and KDM5B: their roles in development and tumorigenesis

“…Indeed, knockdown of KDM5A, KDM5B, and KDM5C abrogates induction of these pro-proliferative cell cycle genes in response to adipogenesis. Future research should delineate the molecular mechanisms underlying the dual role of KDM5A as a gene activator and repressor 22 . Similar to KDM5A, KDM5B plays a decisive role in the regulation of cell fate.…”

KDM5-mediated activation of genes required for mitochondrial biology is necessary for viability inDrosophila

“…The relationship between KDM5A, KDM5B, and tumorigenesis appears to be primarily oncogenic, with a range of cancers showing increased expression of either of these two paralogs. Rather than being linked to the regulation of a single process in malignant cells, KDM5A and KDM5B contribute to many facets of tumorigenesis including the regulation of genes linked to cell cycle control, DNA repair and angiogenesis (Yoo et al, 2022, Ohguchi et al, 2021, Taylor-Papadimitriou and Burchell, 2022, Ohguchi and Ohguchi, 2022. The roles of KDM5C and KDM5D in malignancies are less defined, although, in contrast to KDM5A and KDM5B, it is generally reduction of these proteins that is observed in various cancers, most notably renal carcinomas (Tricarico et al, 2020).…”

“…To date, most attempts to define these links have focused on the canonical histone demethylase activity. However, it is becoming increasingly apparent that KDM5 and other chromatin-modifying proteins also perform important non-catalytic gene regulatory functions (Ohguchi and Ohguchi, 2022, Paroni et al, 2018, Cao et al, 2014, Aubert et al, 2019, Morgan and Shilatifard, 2023. Demethylase-dependent and independent activities of KDM5 proteins have been shown to play roles in both cancer and intellectual disability (Iwase et al, 2007, Vallianatos et al, 2018, Paroni et al, 2018.…”