Abstract
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.
Highlights
Histone modifications are dynamically controlled by chromatin-modifying enzymes that read specific positions and add or remove corresponding covalent modifications
KDMs are divided into two classes according to the type of cofactor used in their catalytic mechanisms, namely flavin adenine dinucleotide (FAD) [5] or α-ketoglutarate (α-KG called 2-oxoglutarate (2-OG)) with iron Fe(II) [6]
Brahma related gene 1 (BRG1) contributes to Breast Cancer (BCa) metastasis via tumor necrosis factor-α (TNF-α) and interferon-gamma (IFN-γ) induced transcription of Mucin 1 (MUC1), which is a pro-metastatic oncoprotein that is aberrantly elevated in highly malignant BCa due to transcriptional upregulation
Summary
Histone modifications are dynamically controlled by chromatin-modifying enzymes that read specific positions and add or remove corresponding covalent modifications. KDM3 proteins are deregulated in skin, hair, and cardiovascular diseases and multiple cancers, including breast, prostate, and colon cancers, and lymphomas, and they have emerged as potential broad-spectrum therapeutic targets. Each of these KDM3 proteins plays differential yet redundant functions in both physiological and pathological processes (Figure 2). (4) KDM3A regulates oncogene expression by binding NRs (e.g., AR [20,30], ER [31,32,33], HIF-1α [24,25]) and modulating downstream signaling (e.g., Wnt/β-catenin signaling [26,34] and Hippo signaling [27]) These proteins regulate gene expression and chromatin dynamics by demethylating H3K9me1/2. There are no reported compounds that are selective for KDM3 subfamily proteins or their isoforms, we have summarized current knowledge and the potential of KDM3 inhibitors as therapeutic agents for cancer treatment
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