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DNA Methylation profiling in luminal breast cancer cells treated with a novel KDM5 inhibitor, 5-aza-2' Deoxycytidine, or both.

ABSTRACT: Recently, the H3K4 demethylase, KDM5B, was shown to be amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here, we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins, either alone, or in combination with the DNA demethylating agent 5-aza-2’ deoxycytidine (DAC). Alone, the KDM5 inhibitor (KDM5i) increased expression of a small number of genes, but when combined with DAC, the drug enhanced the effects of the latter for increasing expression of hundreds of DAC responsive genes. To determine if this combinatorial action was the result of enhanced DNA demethylation, we profiled genome-wide DNA methylation in cells treated with KDM5i, DAC, or both. Methylation levels at approximately 450,000 unique CpG loci were detected using the Infinium Illumina HumanMethylation 450 array. We found that KDM5i did not significantly affect DNA methylation either alone, or in combination with DAC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE97483 | GEO | 2017/12/08

SECONDARY ACCESSION(S): PRJNA381956

REPOSITORIES: GEO

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ChIP-seq analysis of H3K4me3 and H3K27ac localization in breast cancer cells treated with a novel KDM5 inhibitor, , 5-aza-2' Deoxycytidine, or both

Project description:Recently, the H3K4 demethylase, KDM5B, was shown to be amplified and overexpressed in luminal breast cancer, suggesting it might constitute a potential cancer therapy target. Here, we characterize, in breast cancer cells, the molecular effects of a recently developed small-molecule inhibitor of the KDM5 family of proteins, either alone, or in combination with the DNA demethylating agent 5-aza-2’ deoxycytidine (DAC). Alone, the KDM5 inhibitor (KDM5i) increased expression of a small number of genes, but when combined with DAC, the drug enhanced the effects of the latter for increasing expression of hundreds of DAC responsive genes. ChIP-seq studies revealed that KDM5i resulted in the broadening of existing, and creation of thousands of new H3K4me3 domains. When compared to DAC alone, increased promoter and gene body H3K4me3 occupancy at DAC responsive genes was observed in cells treated with the drug combination. Importantly, treatment with either DAC or DAC+KDM5i induced a dramatic increase in H3K27ac at enhancers with an associated significant increase in target gene expression, suggesting a previously unappreciated effect of DAC on transcriptional regulation. Finally, we found that KDM5i could synergize with DAC to reduce the viability of luminal breast cancer cells in in-vitro assays. Our study provides the first look into the molecular effects of novel KDM5i compounds and suggests that combining these with DAC may represent an exciting new approach to epigenetic therapy.

2017-12-08 | GSE97481 | GEO

Gene Expression profiling in luminal breast cancer cells treated with a novel KDM5 inhibitor, 5-aza-2' Deoxycytidine, or both.

2017-12-08 | GSE97482 | GEO

ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer (ChIP-Seq)

Project description:We previously identified KDM5B, encoding a histone H3 lysine 4 (H3K4) demethylase, as an oncogene in estrogen receptor positive (ER+) breast cancer driving endocrine resistance. Here we describe that KDM5A is frequently amplified and overexpressed in basal breast tumors and is associated with chemotherapy resistance. Using CRISPR knockout viability screens -/+ KDM5 inhibition (KDM5i), we found that deletion of the transcription factor ZBTB7A and core SAGA complex increased sensitivity to KDM5i, whereas knockout of RHO-GTPases led to resistance. Integrated ChIP-seq and RNA-seq analyses revealed colocalization of ZBTB7A and KDM5s at promoters with high H3K4me3 signal and dependence of KDM5A binding on ZBTB7A. ZBTB7A knockout had a pleiotropic effect on transcriptional responses to KDM5i, in which it modulates the KDM5i-induced innate immune signaling and NF-kB-regulated genes. ZBTB7A knockout and KDM5i cooperate to alter cell states with KDM5i decreasing basal-like and ZBTB7A knockout inducing mesenchymal-like gene expression patterns. Our work furthers our understanding of KDM5-mediated gene regulation in breast cancer and identifies key pathways that mediate sensitivity to KDM5 inhibition

2024-10-14 | GSE259248 | GEO

ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer (RNA-Seq)

2024-10-14 | GSE259249 | GEO

ZBTB7A is a modulator of KDM5-driven transcriptional networks in basal breast cancer (scRNA-seq)

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ZBTB7A and KDM5 activity co-regulate NF-kB target gene expression and oxidative phosphorylation in triple negative breast cancer

Project description:We previously described that the KDM5B histone H3 lysine 4 (H3K4) demethylase is an oncogene in estrogen receptor-positive breast cancer. Here we report that KDM5A is amplified and overexpressed in basal breast tumors and is associated with chemotherapy resistance. Using CRISPR knockout viability screens -/+ KDM5 inhibition (KDM5i), we found that deletion of the ZBTB7A transcription factor and core SAGA complex sensitized to KDM5i, whereas knockout of RHO-GTPases led to resistance. ChIP-seq and RNA-seq analyses revealed colocalization of ZBTB7A and KDM5A/B at promoters with high H3K4me3 and dependence of KDM5A binding on ZBTB7A. ZBTB7A knockout altered transcriptional response to KDM5i specifically at NF-kB target genes, oxidative phosphorylation, and E2F-driven proliferation pathways. Our work furthers understanding of KDM5-mediated gene regulation in breast cancer and identified key pathways mediating sensitivity to KDM5i.

2024-04-02 | MSV000094452 | MassIVE

RNA-seq of HER2-positive breast cancer BT474 cell line in response to KDM5 ihibition

Project description:Alterations in the histone methylation profiles are observed in various types of cancer and targeting of this epigenetic process has therapeutic potential. Here we provide proof-of-principle that pharmacological targeting of KDM5 histone-demethylases is a new strategy for the personalized treatment of HER2-positive breast cancer. This analysis demonstrates that cells characterized by HER2-positivity are particularly sensitive to KDM5 inhibition. The results are confirmed in an appropriate in vivo model with a close structural analogue (KDM5-inh1A). In selected HER2-positive breast cancer cells, we demonstrate synergistic interactions between KDM5-inh1 and HER2-targeting agents (trastuzumab and lapatinib). In addition, HER2-positive cell lines showing innate/acquired resistance to trastuzumab show sensitivity to KDM5-inh1. The levels of KDM5A/B/C proteins, which are selectively targeted by the agent, have no significant association with KDM5-inh1 responsiveness across our panel of breast cancer cell lines, suggesting the existence of other determinants of sensitivity. Using RNA-sequencing data of the breast cancer cell lines, we generate a gene-expression model, consisting of fifteen genes, which is a robust predictor of KDM5-inh1 sensitivity. In a test set of breast cancers, this model correctly predicts sensitivity to the compound in a large fraction of HER2+ tumors. In conclusion, KDM5 inhibition has potential in the treatment of HER2+ breast cancer and our gene-expression model can be developed into a diagnostic tool to select patients who may benefit from treatments based on KDM5-inhibitors.

2019-02-01 | E-MTAB-7433 | biostudies-arrayexpress

Generic drug screen identifies paracetamol as 5-aza-2’-deoxycytidine sensitizer in head and neck squamous cell carcinoma cells

Project description:Aberrant DNA methylation (5mC) is one of the key characteristics of many cancers including head and neck squamous cell carcinoma (HNSCC). The DNA demethylating agent 5-aza-2’-deoxycytidine (DAC) has anti-cancer therapeutic potential, but its clinical efficacy is currently hindered by dose-limiting side effects. Here we investigated the potential use of DAC in the treatment of HNSCC and show that its efficacy is primarily dependent on the ability of DAC to demethylate DNA. In order to establish whether HNSCC cells can be sensitized to DAC, a panel of 100 generic drugs were screened in combination with DAC. While the 100-drug panel did not sensitise DAC-resistant HNSCC cell lines to DAC treatment, the screen identified that paracetamol (acetaminophen), valproic acid and zinc acetate significantly enhanced DAC efficacy in the DAC-responsive cell lines. DAC and paracetamol were established to work in synergy, allowing DAC to be used at therapeutically relevant low doses (below 500nM). The mechanisms underlying the DAC-paracetamol synergy are multifactorial and encompass both effects of DAC on paracetamol action (alterations in the cyclooxygenase (COX) pathway and mimicry of paracetamol overdose) as well as decreased DNA methylation by paracetamol. Therefore, we propose DAC to be a potential therapeutic in a subset of HNSCC patients with its efficacy significantly increased by use of the common analgesic paracetamol. The DAC-paracetamol synergy should also be considered in cancers with an approved DAC treatment regime.

2018-11-02 | GSE110045 | GEO

Treatment of AML patient samples with decitabine

Project description:Genome wide DNA methylation profiling of AML patient samples treated with PBS or DAC. The Illumina Infinium 450 Human DNA methylation was used to examine the methylation profile of 8 patient samples and 2 cell lines. Genome wide DNA methylation profiling of AML xenografts treated with either PBS control or with decitacine (DAC) alone, cytarabine (Ara-C) alone, DAC and Ara-C together (D+A), DAC followed by Ara-C (D/A) or with Ara-C followed by DAC (A/D).

2013-03-06 | GSE44830 | GEO

BRWD3 targets KDM5/Lid for degradation to maintain H3K4 methylation levels

Project description:Histone modifications are critical for regulating chromatin structure and gene expression. Dysregulation of histone modification levels may contribute to disease development and cancer. Therefore, understanding histone modifications is essential for development and disease. The chromatin-binding protein BRWD3, a known substrate-specificity factor of the Cul4-DDB1 E3 ubiquitin ligase complex, is required for maintaining active histone modification levels. Loss of BRWD3 function causes an increase in H3K4me1 levels. The underline mechanism, however, is unknown. We found that BRWD3 depletion also causes a decrease in H3K4me3 levels. To reveal the mechanism by which BRWD3 regulates the H3K4 methylation levels, we performed BRWD3-IP mass-spectrometry. We identified an interaction between BRWD3 and the lysine-specific demethylase 5 (KDM5/Lid), an enzyme that removes tri- and di- methyl marks from lysine 4 on histone H3. Moreover, analysis of ChIP-seq data revealed that BRWD3 and KDM5 are significantly co-localized throughout the genome. We show that BRWD3 promotes K48-linked ubiquitination of KDM5. Consistent with this, KDM5/Lid is rapidly degraded in a proteasome-dependent manner with a half-life of less than 30 mins. Critically, KDM5/Lid degradation is dependent on both BRWD3 and Cul4. In addition, we have found that BRWD3 is suppressor of Position-effect variegation (PEV). Loss of a single copy of KDM5, however, partially rescues the the BRWD3 PEV phenotype. Our results suggest that BRWD3 targets KDM5/Lid for degradation to ensure the balance of H3K4me levels.

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