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Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.

ABSTRACT: The KDM5/JARID1 family of Fe(II)- and ?-ketoglutarate-dependent demethylases removes methyl groups from methylated lysine 4 of histone H3. Accumulating evidence supports a role for KDM5 family members as oncogenic drivers. We compare the in vitro inhibitory properties and binding affinity of ten diverse compounds with all four family members, and present the crystal structures of the KDM5A-linked Jumonji domain in complex with eight of these inhibitors in the presence of Mn(II). All eight inhibitors structurally examined occupy the binding site of ?-ketoglutarate, but differ in their specific binding interactions, including the number of ligands involved in metal coordination. We also observed inhibitor-induced conformational changes in KDM5A, particularly those residues involved in the binding of ?-ketoglutarate, the anticipated peptide substrate, and intramolecular interactions. We discuss how particular chemical moieties contribute to inhibitor potency and suggest strategies that might be utilized in the successful design of selective and potent epigenetic inhibitors.

SUBMITTER: Horton JR

PROVIDER: S-EPMC4958579 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.

Horton John R JR Liu Xu X Gale Molly M Wu Lizhen L Shanks John R JR Zhang Xing X Webber Philip J PJ Bell Joshua S K JSK Kales Stephen C SC Mott Bryan T BT Rai Ganesha G Jansen Daniel J DJ Henderson Mark J MJ Urban Daniel J DJ Hall Matthew D MD Simeonov Anton A Maloney David J DJ Johns Margaret A MA Fu Haian H Jadhav Ajit A Vertino Paula M PM Yan Qin Q Cheng Xiaodong X

Cell chemical biology 20160714 7

The KDM5/JARID1 family of Fe(II)- and α-ketoglutarate-dependent demethylases removes methyl groups from methylated lysine 4 of histone H3. Accumulating evidence supports a role for KDM5 family members as oncogenic drivers. We compare the in vitro inhibitory properties and binding affinity of ten diverse compounds with all four family members, and present the crystal structures of the KDM5A-linked Jumonji domain in complex with eight of these inhibitors in the presence of Mn(II). All eight inhibi ...[more]

PMID: 27427228

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Project description:ObjectiveAberrant activity of androgen receptor (AR) is the primary cause underlying development and progression of prostate cancer (PCa) and castration-resistant PCa (CRPC). Androgen signaling regulates gene transcription and lipid metabolism, facilitating tumor growth and therapy resistance in early and advanced PCa. Although direct AR signaling inhibitors exist, AR expression and function can also be epigenetically regulated. Specifically, lysine (K)-specific demethylases (KDMs), which are often overexpressed in PCa and CRPC phenotypes, regulate the AR transcriptional program.MethodsWe investigated LSD1/UTX inhibition, two KDMs, in PCa and CRPC using a multi-omics approach. We first performed a mitochondrial stress test to evaluate respiratory capacity after treatment with MC3324, a dual KDM-inhibitor, and then carried out lipidomic, proteomic, and metabolic analyses. We also investigated mechanical cellular properties with acoustic force spectroscopy.ResultsMC3324 induced a global increase in H3K4me2 and H3K27me3 accompanied by significant growth arrest and apoptosis in androgen-responsive and -unresponsive PCa systems. LSD1/UTX inhibition downregulated AR at both transcriptional and non-transcriptional level, showing cancer selectivity, indicating its potential use in resistance to androgen deprivation therapy. Since MC3324 impaired metabolic activity, by modifying the protein and lipid content in PCa and CRPC cell lines. Epigenetic inhibition of LSD1/UTX disrupted mitochondrial ATP production and mediated lipid plasticity, which affected the phosphocholine class, an important structural element for the cell membrane in PCa and CRPC associated with changes in physical and mechanical properties of cancer cells.ConclusionsOur data suggest a network in which epigenetics, hormone signaling, metabolite availability, lipid content, and mechano-metabolic process are closely related. This network may be able to identify additional hotspots for pharmacological intervention and underscores the key role of KDM-mediated epigenetic modulation in PCa and CRPC.

Dataset Information

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.

Publications

Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.

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