Lysine Demethylase 5A Is Required for MYC-Driven Transcription in Multiple Myeloma

Abstract

Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3K4 trimethylation, a histone mark associated with activate gene transcription. We identify that KDM5A interacts with the P-TEFb complex and cooperates with MYC to control MYC targeted genes in multiple myeloma (MM) cells. We develop a cell-permeable and selective KDM5 inhibitor, JQKD82, that increases histone H3K4me3 but paradoxically inhibits downstream MYC-driven transcriptional output in vitro and in vivo. Using genetic ablation together with our inhibitor, we establish that KDM5A supports MYC target gene transcription independent of MYC itself, by supporting TFIIH (CDK7)-and P-TEFb (CDK9)mediated phosphorylation of RNAPII.These data identify KDM5A as a unique vulnerability in MM functioning through regulation of MYC-target gene transcription, and establish JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for MM.

Bone Marrow Stroma-Induced Transcriptome and Regulome Signatures of Multiple Myeloma

“…In contrast to acquired drug resistance, de novo drug resistance occurs quickly and is reversible, suggesting that epigenetic mechanisms assume a critical role in regulating the transcription program underlying the resistance [ 3 ]. Recent literature has documented several chromatin regulators in drug resistance and myelomagenesis [ 9 , 10 , 11 , 12 , 13 , 14 , 15 ], including in the context of the BM microenvironment [ 5 , 16 ]. However, few have investigated the contribution of chromatin reorganization to the BMSC-induced transcription changes in MM cells and the associated regulatory mechanisms linked to de novo drug resistance.…”

Diverse Functions of KDM5 in Cancer: Transcriptional Repressor or Activator?

“…Similar to the function of Lid in the developmental genes in Drosophila cells, we recently showed that KDM5A positively regulates its target genes via H3K4me3 demethylation in mammalian cells [35]. KDM5A coexists with MYC and the components of the transcriptional machinery, including CDK7, CDK9, and RNAPII, across the genome of multiple myeloma cells [35]. Importantly, KDM5A depletion and a selective catalytic inhibitor of KDM5 were found to reduce the expression of MYC target genes, concomitant with increased H3K4me3 and reduced Ser2/Ser5-phosphorylated RNAPII at the MYC target gene loci [35].…”

“…Based on these findings, researchers proposed that H3K4me3 demethylation by Lid is required for resetting the chromatin state and starting a new transcription cycle, the disruption of which leads to transcription failure [56]. Similar to the function of Lid in the developmental genes in Drosophila cells, we recently showed that KDM5A positively regulates its target genes via H3K4me3 demethylation in mammalian cells [35]. KDM5A coexists with MYC and the components of the transcriptional machinery, including CDK7, CDK9, and RNAPII, across the genome of multiple myeloma cells [35].…”

“…Importantly, KDM5A depletion and a selective catalytic inhibitor of KDM5 were found to reduce the expression of MYC target genes, concomitant with increased H3K4me3 and reduced Ser2/Ser5-phosphorylated RNAPII at the MYC target gene loci [35]. We further demonstrated that excessive levels of H3K4me3 at the transcription start site (TSS)proximal nucleosomes lock TFIID via TAF3 anchoring, leading to hindered TFIIH and P-TEFb activities [35]. Accordingly, we proposed a model in which KDM5A supports the transcription of MYC target genes by transiently removing H3K4me3, thereby allowing for the release of TFIID and the phosphorylation of RNAPII at these gene loci (Figure 2C) [35].…”

“…KDM5A coexists with MYC and the components of the transcriptional machinery, including CDK7, CDK9, and RNAPII, across the genome of multiple myeloma cells [35]. Importantly, KDM5A depletion and a selective catalytic inhibitor of KDM5 were found to reduce the expression of MYC target genes, concomitant with increased H3K4me3 and reduced Ser2/Ser5-phosphorylated RNAPII at the MYC target gene loci [35]. We further demonstrated that excessive levels of H3K4me3 at the transcription start site (TSS)proximal nucleosomes lock TFIID via TAF3 anchoring, leading to hindered TFIIH and P-TEFb activities [35].…”