Therapeutic potential of inhibiting histone 3 lysine 27 demethylases: a review of the literature

Abstract

Histone 3 lysine 27 (H3K27) demethylation constitutes an important epigenetic mechanism of gene activation. It is mediated by the Jumonji C domain-containing lysine demethylases KDM6A and KDM6B, both of which have been implicated in a wide myriad of diseases, including blood and solid tumours, autoimmune and inflammatory disorders, and infectious diseases. Here, we review and summarise the pre-clinical evidence, both in vitro and in vivo, in support of the therapeutic potential of inhibiting H3K27-targeting demethylases, with a focus on the small-molecule inhibitor GSK-J4. In malignancies, KDM6A/B inhibition possesses the ability to inhibit proliferation, induce apoptosis, promote differentiation, and heighten sensitivity to currently employed chemotherapeutics. KDM6A/B inhibition also comprises a potent anti-inflammatory approach in inflammatory and autoimmune disorders associated with inappropriately exuberant inflammatory and autoimmune responses, restoring immunological homeostasis to inflamed tissues. With respect to infectious diseases, KDM6A/B inhibition can suppress the growth of infectious pathogens and attenuate the immunopathology precipitated by these pathogens. The pre-clinical in vitro and in vivo data, summarised in this review, suggest that inhibiting H3K27 demethylases holds immense therapeutic potential in many diseases.

Upregulation of lysine‐specific demethylase 6B aggravates inflammatory pain through H3K27me3 demethylation‐dependent production of TNF‐α in the dorsal root ganglia and spinal dorsal horn in rats

“…H3K27me3 is a critical epigenetic event frequently associated with gene repression. KDM6B is a member of JmjC histone demethylases family that specifically demethylate the trimethylate lysine at position 27 of H3 protein to regulate correlated gene expression 39,40 and involves in the proinflammatory gene production 13,17,22,35,41 . In our current study, we found that intraplantar injection of CFA led to increase in the expression of KDM6B and a reduction in the level of H3K27me3 in both the DRG and spinal dorsal horn.…”

“…Compelling evidence has highlighted the proinflammatory role of KDM6B in various inflammatory diseases by regulating the expression of several NF‐κB‐dependent cytokines 13,35 . The TNF‐α has been demonstrated as a potent mediator in the pathogenesis of variety of chronic pain 45–48 .…”

“…The upregulation of KDM6B demethylates H3K27me3 to H3K27me2 or H3K27me1, thus leading to the removal of the methylation mark from H3K27 and actives gene transcription 11,12 . Compelling evidence suggests that KDM6B is involved in the regulation of cell differentiation and inflammation by targeting distinct transcription factors which control cytokine gene expression 10,13,14 . KDM6B depletion or inhibition decreases the expression of toll‐like receptor 4 and negates downstream NF‐κB proinflammatory signaling and subsequently ameliorates lipopolysaccharide‐induced inflammation in a mastitis model 15–17 .…”

Six‐transmembrane epithelial antigen of prostate 3 (STEAP3) is a potential prognostic biomarker in clear cell renal cell carcinoma that correlates with M2 macrophage infiltration and epithelial–mesenchymal

“…Moreover, we predicted GSK‐J4 and tozasertib as the sensitive drugs based on STEAP3 expression. GSK‐J4 is a small‐molecule inhibitor of histone 3 lysine 27 demethylation, which exerts anticancer effects in various tumors and has anti‐inflammatory effects 39 . Tozasertib (MK‐0457) is a pan‐aurora kinase inhibitor, which suppresses cell proliferation and induces apoptosis in both preclinical studies and clinical settings 40 .…”

GSK‐J4: An H3K27 histone demethylase inhibitor, as a potential anti‐cancer agent

“…It has been shown to target different signaling molecules via inhibiting JMJD3, which gives GSK‐J4 its anti‐cancer properties. The in‐vivo and in‐vitro studies from pre‐clinical data show that GSK‐J4 has therapeutic potential in diseases ranging from cancer, inflammation, autoimmune diseases and infectious diseases 28 . In this review, the aim is to summarize the existing literature on the effect of GSK‐J4, focusing on different cancer types, the in‐vivo studies, and studies involving the combination of GSK‐J4 with a conventional anti‐cancer drug.…”