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SMYD2 methylates KDM5A restricting its demethylase activity on the genome (and driving proliferation)

ABSTRACT: Members of the KDM5 family of Jumonji histone demethylases have been implicated in a variety of human diseases including multiple cancers. The regulation of KDM5 enzyme levels and activity, however, is poorly understood. Here we report that KDM5A is methylated by SMYD2 and that this methylation impacts histone demethylase activity. A mutant KDM5A that can no longer be methylated at K1063 exhibits unique genomic sites of action, demethylates H3K4me3 more robustly and at new loci, has unique transcriptional effects and distinct protein-protein interactions. As a result, a number of cell proliferation pathways are affected and cancer cell growth is blunted. This study illustrates the functional consequences of post-translational modifications of lysine residues in enzymes impacting genomic histone demethylation, gene expression and signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297612 | GEO | 2026/05/27

REPOSITORIES: GEO

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SMYD2 methylates KDM5A restricting its demethylase activity on the genome (and driving proliferation

Project description:Members of the KDM5 family of Jumonji histone demethylases have been implicated in a variety of human diseases including multiple cancers. The regulation of KDM5 enzyme levels and activity, however, is poorly understood. Here we report that KDM5A is methylated by SMYD2 and that this methylation impacts histone demethylase activity. A mutant KDM5A that can no longer be methylated at K1063 exhibits unique genomic sites of action, demethylates H3K4me3 more robustly and at new loci, has unique transcriptional effects and distinct protein-protein interactions. As a result, a number of cell proliferation pathways are affected and cancer cell growth is blunted. This study illustrates the functional consequences of post-translational modifications of lysine residues in enzymes impacting genomic histone demethylation, gene expression and signaling.

2026-05-27 | GSE297614 | GEO

Genome-wide maps of KDM5A/JARID1A/RBP2 in mouse ES cells.

Project description:We report the identification of genomic regions bound by KDM5A in mouse embryonic stem (ES) cells and define the functional categories that these regions represent. KDM5A modifies methylated lysine residues on histone tails. We developed anti-KDM5A antibodies and set to detect genomic regions enriched with these antibodies using cells with normal Kdm5a or cells from Kdm5a knockout mice as a control. We found high enrichment with the KDM5A antibodies in normal cells when compared with the genomic background. We found striking identity in the regions enriched with these antibodies in normal cells when compared with the total genomic DNA or with KDM5A ChIP assays from Kdm5a KO cells, showing that the antibodies are specific. Examination of target genes in ES cells

2012-10-04 | E-GEOD-28343 | biostudies-arrayexpress

Genome-wide maps of KDM5A/JARID1A/RBP2 in mouse ES cells.

2012-10-04 | GSE28343 | GEO

Chip-chip from MDA-MB-231 cells with SMYD2 and EZH2

Project description:The histone methyl transferase EZH2 and SMYD2 are master epigenetic regulators involved in histone methylation and gene transcription repression. Here, we report that SMYD2 and EZH2 may act as a complex in transcriptional regulation and are involved in the progression of breast cancer. ChIP-on-chip assays were performed to find unique promoters co-targeted by EZH2 and SMYD2 in MDA-MB-231 cells.

2019-11-03 | GSE126055 | GEO

Quantitative profiling of the enzymatic activity of the protein lysine mono-methyltransferase SMYD2 using SILAC-based proteomics

Project description:The significance of non-histone lysine methylation in cell biology and human disease is an emerging area of research exploration, and small molecule inhibitors that selectively and potently target “writers” and “erasers” of methyl-lysine, such as the protein lysine mono-methyltransferase SMYD2, are active areas of drug discovery. It is therefore essential to clarify the substrates of these enzymes in cellular contexts in order to advance and to correctly understand the cellular mechanism(s) of action of these targets. Here, using stable isotopic labelling of amino acids in cell culture (SILAC) coupled with immunoaffinity enrichment of mono-methyl-lysine (Kme1) peptides and mass spectrometry, we report the most comprehensive and large-scale proteomic study of protein mono-methylation, comprising a total of 1032 Kme1 sites identified in esophageal squamous cell carcinoma (ESCC) cells and 1861 Kme1 sites in ESCC cells overexpressing SMYD2. Among these sites was a subset of 35 robust Kme1 sites that were potently down-regulated by both shRNA-mediated knockdown of SMYD2 and LLY-507, a small molecule inhibitor of SMYD2. In addition, we report specific protein sequence motifs that were enriched in Kme1 sites and that were also directly regulated by endogenous SMYD2 activity, indicating that the diversity of SMYD2 substrate specificity of SMYD2 exceeds previous expectations. Furthermore, we reveal that BTF3 and PDAP1 are novel and direct substrates of SMYD2, as well as AHNAK and AHNAK2, two large and highly-repetitive proteins directly and extensively mono-methylated by SMYD2 at several lysine residues. Collectively, our findings provide novel quantitative and insights into the cellular activity and substrate recognition of SMYD2 as well as the global landscape and regulation of protein mono-methylation in cells.

2016-01-11 | PXD002405 | Pride

KDM5A suppresses PML-RARα target gene expression and APL differentiation through repressing H3K4me2

Project description:Epigenetic abnormalities are frequently involved in the initiation and progression of cancers including acute myeloid leukemia (AML). A subtype of AML, Acute promyelocytic leukemia (APL), is mainly driven by a specific oncogenic fusion event of PML-RARα. PML-RARα was reported as a transcription repressor through the interaction with NCoR/HDAC complexes leading to the mis-suppression of its target genes and differentiation blockage. While previous studies were mainly focused on the connection of histone acetylation, it is still largely unknown whether alternative epigenetics mechanisms are involved in APL progression. KDM5A is a demethylase of histone H3 lysine 4 di- and tri- methylations (H3K4me2/3) and a transcription corepressor. Here, we found that the loss of KDM5A led to APL NB4 cell differentiation and retarded growth. Mechanistically, through epigenomics and transcriptomics analyses, we detected KDM5A binding in 1,889 genes, with the majority of the binding events at promoter regions. KDM5A suppressed the expression of 621 genes, including 42 PML-RARα target genes primarily by controlling the H3K4me2 in the promoters and 5’ end intragenic regions. In addition, a recently reported pan-KDM5 inhibitor, CPI-455 on its own could phenocopy the differentiation effects as KDM5A loss in NB4 cells. CPI-455 treatment or KDM5A knockout could greatly sensitize NB4 cells to ATRA induced differentiation. Our findings indicated that KDM5A contributed to the differentiation blockage in the APL cell line NB4, and inhibition of KDM5A could greatly potentiate NB4 differentiation.

2021-04-01 | GSE152397 | GEO

Transcription profiling of human embryonic kidney cells overexpressing SMYD2 to identify which genes are regulated by SMYD2 through its histone lysine methylation activity

Project description:Identification of SMYD2 target genes - The objective of this aim is to identify which genes are regulated by SMYD2 through its histone lysine methylation activity. It is well established that post-translational modification of nucleosomal histones (H2A, H2B, H3 and H4), such as methylation, acetylation and phosphorylation are central to the proper control of gene expression

2008-02-05 | E-MEXP-963 | biostudies-arrayexpress

Transcriptome profiling of B-cell lymphoma cells with pharmacological inhibition of KDM5A/B by using the inhibitor JQKD82

Project description:Histone methylation critically controls the progression of human diseases, including infections and cancers. Our study reported that histone lysine demethylases (KDMs) in the KDM5 family KDM5A/B play profound roles in suppressing lytic reactivation of oncogenic human herpesvirus 8 (HHV-8), i.e., Kaposi's sarcoma-associated herpesvirus (KSHV), a human gamma-herpesvirus and an etiological agent of multiple malignancies. During KSHV lytic reactivation from latency, host innate immune responses are also activated, which is expected to favor the tumor cell killing by generating the additional oncolytic effects. To further study the systemic effect of KSHV on host immune response under the regulation of KDM5A/B, we performed the transcriptome profiling analysis for both KSHV-infected BCBL-1 vs KSHV-negative BJAB cells with or without JQKD82 treatment by RNA-seq. Our RNA-seq analysis and further experimental validation suggested that the KDM5 inhibitor JQKD82 is capable of inducing antiviral/antitumor innate immune responses in KSHV-negative B-cell lymphomas, but such effects are more striking in KSHV-positive B-cell lymphomas likely due to KSHV lytic reactivation that further triggers the innate immune activation in tumor cells.

2026-03-10 | GSE310839 | GEO

ChIP-seq analyses for KDM5A, H3K4me3, RNAPII and TAF3 in human multiple myeloma cell line MM.1S

Project description:Recent studies have highlighted the oncogenic roles of KDM5A; however, its molecular mechanism has not been fully delineated. Here we identifies KDM5A as a transcriptional activator of MYC target genes in multiple myeloma (MM). Genetic ablation of KDM5A or pharmacologic inhibition of KDM5 by novel inhibitor JQKD82 impairs MM cell growth. Gene expression profile reveals that JQKD82 decreases expression of MYC targets. Expression of MYC targets is similarly downregulated by KDM5A depletion, but little affected by KDM5B knockdown. Mechanistically, KDM5A co-localizes with MYC across the genome, and KDM5A and MYC coordinately promote MYC target gene transcription. The treatment with JQKD82 reduces phosphorylation level of RNA polymerase II (RNAPII), resulting in RNAPII pausing, accompanied by hyper-H3K4me3 status at the MYC loci. Finally, we shows that JQKD82 exerts anti-MM activity and prolongs overall survival in vivo mouse xenograft models. Our results delineate KDM5A function that reinforces MYC transcriptional program, and identify KDM5A as a potential therapeutic target in MM.

2021-03-22 | GSE148046 | GEO

SMYD2 overexpression in Neonatal rat ventricular cardiomyocytes

Project description:From this array we would like to know the role of Smyd2 on hypoxic regulated genes mainly angiogenic pathway. We performed overexpressions of Smyd2 and beta galactosidase by adenoviral approach and knockdown of HIF1 and Smyd2 were performed by lipofectamine RNAiMAX.Cardiomyocytes were isolated from neonatal rats at P3.

2025-03-01 | GSE256036 | GEO

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