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.

Keywords: KDM5; MYC; RNA polymerase II; cancer; epigenetic regulator; histone demethylase.

Figure 1

Domain structure of the KDM5 protein family. The functions of each domain are also presented. JmjN: Jumonji N domain; JmjC: Jumonji C domain; ARID: AT-rich interaction domain; PHD: plant homeodomain; C₂HC₂: C₅HC₂ zinc finger.

Figure 2

Transcriptional regulation by KDM5. (A) Pre-initiation complex assembly is mediated by the selective anchoring of the basal transcription factor TFIID to the core promoter via TAF3 binding to H3K4me3. KDM5 proteins remove H3K4me3, thereby preventing transcription. (B) KDM5B functions as a scaffold protein and recruits the H3K9 methyltransferase, SETDB1, thereby suppressing retroelement expression by adding H3K9me3 [44]. (C) After pre-initiation complex formation, KDM5A supports the transcription of MYC target genes via the timely removal of H3K4me3, thereby allowing for the release of TFIID and for the phosphorylation of RNA polymerase II (RNAPII). KDM5A inhibition blocks H3K4me3 demethylation, thereby locking TFIID via TAF3 anchoring and impairing the activities of TFIIH and P-TEFb, which may be mediated by TAF7 [35]. (D) KDM5A promotes CLOCK–BMAL1-mediated transcription by inhibiting HDAC1 [52].

Figure 3

Multiple functions of KDM5A in cancer. (A) In pRb-deficient cells, KDM5A promotes tumorigenesis by cell cycle progression and differentiation block. (B) KDM5A and MYC coordinately promote tumorigenesis by activating MYC target gene expression. (C) KDM5A and RBP-J promote small cell lung cancer (SCLC) by inducing the expression of neuroendocrine genes through the repression of Notch target genes. (D) NUP98–KDM5A induces leukemogenesis by activating the expression of acute myeloid leukemia (AML)-associated transcription factors (TFs) and CDK6, as well as the JAK-STAT pathway. (E) KDM5A confers drug resistance by chromatin alterations. (F) KDM5A elevates PDL1 expression by activating the PI3K–AKT–S6K1 cascade through the downregulation of PTEN.

Figure 4

The functions of KDM5B in each type of cancer. (A) In estrogen receptor (ER)⁺ breast cancer, KDM5B promotes tumor growth by repressing BRCA1 and HOXA5 and by inducing cyclin D1 through the repression of let-7e. KDM5B induces the luminal transcriptional program by downregulating basal genes and upregulating luminal genes. KDM5B also contributes to therapeutic resistance by inducing transcriptomic heterogeneity. KDM5B and ER coordinately stimulate E2-dependent tumor growth. KDM5B and EMSY induce tumor invasiveness by repressing miR-31. (B) In melanoma, KDM5B induces cancer stem cell-like features and multidrug resistance by promoting oxidative phosphorylation. KDM5B also inhibits the anti-melanoma immune response by repressing interferon-stimulated genes (ISGs) in cooperation with SETDB1. (C) In prostate cancer, KDM5B activates androgen receptor (AR) target genes in cooperation with AR. KDM5B also activates PI3K/AKT signaling by upregulating PIK3CA. PI3K/AKT signaling suppresses miR-137, which consequently increases KDM5B expression, forming a positive feedback loop. (D) In non-small cell lung cancer (NSCLC), KDM5B induces epithelial–mesenchymal transition (EMT) by increasing ZEB1 and ZEB2 through repressing the miR-200. KDM5B also confers radioresistance by recruiting DNA repair factors to DNA damage sites. In addition, KDM5B induces cancer stem cell-like features by activating c-MET signaling.

Figure 5

The loss-of-function of KDM5C promotes clear cell renal cell carcinoma (ccRCC). The loss-of-function of KDM5C increases genomic instability in ccRCC by heterochromatin dysregulation through the upregulation of non-coding (nc)RNAs. KDM5C deficiency also promotes angiogenesis. In VHL-deficient ccRCC cells, KDM5C deficiency promotes tumor growth by suppressing the tumor suppressor ISGF3, which is induced by HIF.