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

Abstract

Aberrant epigenetic modifications are emerging as potent drivers of tumor initiation and progression. The deregulation of H3K27me3 marks has shown to play an important role in cancer progression in several cancers. The H3K27me3 mark is associated with gene silencing. The reversible nature of these epigenetic aberrations makes them an important target for treating cancer. GSK‐J4 is a histone demethylase inhibitor that inhibits the JMJD3/UTX enzyme, which results in the upregulation of H3K27me3 levels. In this review, the anti‐cancer properties of GSK‐J4 have been summarized, the various molecular pathways targeted, in‐vivo studies, and drug combination studies in different cancer models. GSK‐J4 targeted pathways like apoptosis, cell cycle, invasion, migration, DNA damage repair, metabolism, oxidative stress, stemness, etc. GSK‐J4 is a promising candidate alone and in combination with other conventional anti‐cancer drugs against different cancer types.

An Imbalance in Histone Modifiers Induces tRNA-Cys-GCA Overexpression and tRF-27 Accumulation by Attenuating Promoter H3K27me3 in Primary Trastuzumab-Resistant Breast Cancer

“…GSK-J4, developed as a specific inhibitor of KDM6A/B to enhance H3K27 methylation, has demonstrated anti-cancer abilities by reducing tumor cell proliferation and inducing apoptosis in various studies [ 16 , 17 , 18 , 19 ]. This inhibitor may also play a role in decreasing tRNA transcription ( Figure 5 a).…”

Targeting histone demethylases JMJD3 and UTX: selenium as a potential therapeutic agent for cervical cancer

“…Selenium inhibits the expression of JMJD3 and UTX, preventing their demethylation of histone H3K27 and resulting in more condensed chromatin and suppressed gene expression. On the other hand, GSK-J4 directly inhibits the enzymatic activity of JMJD3 and UTX, leading to an increased trimethylation modification of histone H3K27, compacting chromatin, and suppressing gene expression [ 49 , 50 ]. It is important to note that while both selenium and GSK-J4 affect histone demethylase function, their mechanisms of action differ.…”

Antitumoral Potential of the Histone Demethylase Inhibitor GSK-J4 in Retinoblastoma

“…As a potential anticancer agent, GSK-J4 has been reported to significantly affect cell growth by influencing the cell cycle. 46 Notably, in different types of cancer (even within different cell lines of the same cancer), the cell cycle phases arrested by GSK-J4 vary. In acute myeloid leukemia, GSK-J4 significantly arrested the cell cycle at the G0/G1 phase in the Kasumi-1 cell line, whereas it arrested the cell cycle at the S phase in the KG-1a cell line.…”