The KDM4 subfamily H3K9 histone demethylases are epigenetic regulators that control chromatin structure and gene expression by demethylating histone H3K9, H3K36, and H1.4K26. The KDM4 subfamily mainly consists of four proteins (KDM4A‐D), all harboring the Jumonji C domain (JmjC) but with differential substrate specificities. KDM4A‐C proteins also possess the double PHD and Tudor domains, whereas KDM4D lacks these domains. KDM4 proteins are overexpressed or deregulated in multiple cancers, cardiovascular diseases, and mental retardation and are thus potential therapeutic targets. Despite extensive efforts, however, there are very few KDM4‐selective inhibitors. Defining the exact physiological and oncogenic functions of KDM4 demethylase will provide the foundation for the discovery of novel potent inhibitors. In this review, we focus on recent studies highlighting the oncogenic functions of KDM4s and the interplay between KDM4‐mediated epigenetic and metabolic pathways in cancer. We also review currently available KDM4 inhibitors and discuss their potential as therapeutic agents for cancer treatment.

Lysine-specific histone demethylase 3 (KDM3) subfamily proteins are H3K9me2/me1 histone demethylases that promote gene expression. The KDM3 subfamily primarily consists of four proteins (KDM3A−D). All four proteins contain the catalytic Jumonji C domain (JmjC) at their C-termini, but whether KDM3C has demethylase activity is under debate. In addition, KDM3 proteins contain a zinc-finger domain for DNA binding and an LXXLL motif for interacting with nuclear receptors. Of the KDM3 proteins, KDM3A is especially deregulated or overexpressed in multiple cancers, making it a potential cancer therapeutic target. However, no KDM3A-selective inhibitors have been identified to date because of the lack of structural information. Uncovering the distinct physiological and pathological functions of KDM3A and their structure will give insight into the development of novel selective inhibitors. In this review, we focus on recent studies highlighting the oncogenic functions of KDM3A in cancer. We also discuss existing KDM3A-related inhibitors and review their potential as therapeutic agents for overcoming cancer.

Glioblastoma is the most lethal brain tumor and its pathogenesis remains incompletely understood. KDM4C is a histone H3K9 demethylase that contributes to epigenetic regulation of both oncogene and tumor suppressor genes and is often overexpressed in human tumors, including glioblastoma. However, KDM4C’s roles in glioblastoma and the underlying molecular mechanisms remain unclear. Here, we show that KDM4C knockdown significantly represses proliferation and tumorigenesis of glioblastoma cells in vitro and in vivo that are rescued by overexpressing wild-type KDM4C but not a catalytic dead mutant. KDM4C protein expression is upregulated in glioblastoma, and its expression correlates with c-Myc expression. KDM4C also binds to the c-Myc promoter and induces c-Myc expression. Importantly, KDM4C suppresses the pro-apoptotic functions of p53 by demethylating p53K372me1, which is pivotal for the stability of chromatin-bound p53. Conversely, depletion or inhibition of KDM4C promotes p53 target gene expression and induces apoptosis in glioblastoma. KDM4C may serve as an oncogene through the dual functions of inactivation of p53 and activation of c-Myc in glioblastoma. Our study demonstrates KDM4C inhibition as a promising therapeutic strategy for targeting glioblastoma.

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The significance of glutamine in cancer metabolism has been extensively studied. Cancer cells consume an excessive amount of glutamine to facilitate rapid proliferation. Thus, glutamine depletion occurs in various cancer types, especially in poorly vascularized cancers. This makes glutamine synthetase (GS), the only enzyme responsible for de novo synthesizing glutamine, essential in cancer metabolism. In cancer, GS exhibits pro-tumoral features by synthesizing glutamine, supporting nucleotide synthesis. Furthermore, GS is highly expressed in the tumor microenvironment (TME) and provides glutamine to cancer cells, allowing cancer cells to maintain sufficient glutamine level for glutamine catabolism. Glutamine catabolism, the opposite reaction of glutamine synthesis by GS, is well known for supporting cancer cell proliferation via contributing biosynthesis of various essential molecules and energy production. Either glutamine anabolism or catabolism has a critical function in cancer metabolism depending on the complex nature and microenvironment of cancers. In this review, we focus on the role of GS in a variety of cancer types and microenvironments and highlight the mechanism of GS at the transcriptional and post-translational levels. Lastly, we discuss the therapeutic implications of targeting GS in cancer.