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Effect of DOT1L inhibition on gene expression in SW1990 pancreatic cancer cells

ABSTRACT: Histone methyltransferase DOT1L plays a critical role in the regulation of gene expression through methylation of histone H3 at lysine 79 (H3K79), a modification associated with active transcription. However, its function in pancreatic ductal adenocarcinoma (PDAC) remains incompletely understood. In this study, we investigated the transcriptional impact of DOT1L in SW1990 pancreatic cancer cells using EPZ-5676, a selective DOT1L inhibitor. Treatment with EPZ-5676 resulted in widespread transcriptional changes, indicating a key regulatory role of DOT1L in maintaining the gene expression profile of SW1990 cells. Through RNA-seq analysis, we identified differentially expressed genes between the untreated control and EPZ-5676-treated cells, implicating DOT1L in pathways involved in cell proliferation, differentiation, and tumor progression. These findings suggest that DOT1L-mediated H3K79 methylation contributes to the transcriptional landscape of pancreatic cancer cells and may represent a potential therapeutic target.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303903 | GEO | 2026/07/28

REPOSITORIES: GEO

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Genome-wide identification of DOT1L-regulated targets via H3K79me2 modification in SW1990 pancreatic cancer cells

Project description:Disruption of epigenetic regulation plays a pivotal role in pancreatic cancer progression, yet the genome-wide targets of DOT1L-mediated histone H3 lysine 79 dimethylation (H3K79me2) remain poorly defined. In this study, we investigated the epigenetic landscape regulated by DOT1L in SW1990 pancreatic ductal adenocarcinoma cells. Cells were treated with EPZ-5676, a selective DOT1L inhibitor, or vehicle control, followed by chromatin immunoprecipitation sequencing (ChIP-seq) using an H3K79me2-specific antibody. We identified differentially enriched regions between EPZ-5676-treated and untreated cells, reflecting global loss of H3K79me2 upon DOT1L inhibition. Integration with gene annotation data revealed putative DOT1L-regulated genes involved in transcriptional regulation, cell proliferation, and cancer signaling pathways. These findings provide insight into the role of DOT1L in maintaining the active chromatin state and transcriptional programs in pancreatic cancer cells and highlight potential therapeutic targets in epigenetic intervention.

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DOT1L-mediated CDK9 methylation is essential for DNA double-strand break repair

Project description:P-TEFb is a key regulator of transcription elongation and is composed of cyclin-dependent kinase 9 (CDK9) and cyclin T1. DOT1L is a histone H3K79 methyltransferase. Here, we show that treatment with the DOT1L inhibitor EPZ-5676 induces transcriptome changes in HCT116 cells. We further demonstrate that DOT1L methylates CDK9 at lysine 56 and that CDK9 methylation-deficient mutant K56A reshapes genome-wide CDK9 occupancy. Notably, changes in CDK9 occupancy are particularly pronounced at double-strand break (DSB)-related genes and are associated with the regulation of their transcription. This idataset includes RNA-seq and ChIP-seq data generated from HCT116 cells.

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DOT1L-mediated CDK9 methylation is essential for DNA double-strand break repair [RNA-seq]

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DOT1L inhibition exerts anti-tumor effects through activating interferon signaling in breast cancer cells

Project description:DOT1L, a histone H3 lysine 79 (H3K79) methyltransferase, is a potential therapeutic target in various malignancies. In the current study, we aimed to clarify the antitumor effect of DOT1L inhibition in breast cancer. Treatment with DOT1L inhibitors (SGC0942, EPZ-5676) suppressed proliferation and induced cell cycle arrest and apoptosis in estrogen receptor (ER)-positive/HER2-negative cancer cells (MCF7) as well as in ER-negative/HER2-positive cancer cells (SKBR3). Transcriptome and epigenome analysis revealed that DOT1L inhibition activated transcription of a number of interferon (IFN)-related genes (IRGs) in both cell lines. Our data suggest that the anti-breast cancer cell effect of DOT1L inhibition is mediated multiple mechanisms including activation of innate immune signaling.

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DOT1L inhibition with EPZ-5676 in human articular chondrocytes from 5 non-OA hip fracture patients

Project description:To identify DOT1L targets, associated signaling pathways and networks in chondrocytes, we used genome-wide gene expression microarray analysis in human articular chondrocytes of 5 different donors (without known or documented joint disease) treated with EPZ-5676 or vehicle for 4 days. It is known that DOT1L inhibitors require longer time of treatment in order to show effect and influence the expression of MLL target genes in leukemia cells, but we opted for this relatively short inhibition time to be able to identify early changes induced by DOT1L inhibition. Human articular chondrocytes were obtained from 5 non-OA hip fracture patients. The cells were treated with 3 Î¼M EPZ-5676 or vehicle (DMSO) for 4 days.

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Project description:BJ fibroblasts were grown in the continued presence of either rapamycin, the DOT1L inhibitor EPZ-5676, rapamycin + EPZ-5676, or control treatment, and collected for RNA-seq at young-quiescent, intermediate-quiescent, or senescent cell states.

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Dual function of DOT1L suppresses tumor intrinsic immunogenicity in Hepatocellular carcinoma [RNA-seq]

Project description:Checkpoint inhibitor therapy for Hepatocellular carcinoma (HCC) remains limited in patients’ overall response rate. Discovery and development of more effective combinatorial approaches in HCC checkpoint immunotherapy is urgent. Here, through CPlSPR/Cas9 genetic screens, we identify DOT1L as a versatile epigenetic factor that functions to suppress anti-tumor immunity through a dual mechanism. Depletion of DOT1L induces the expression of transposable elements and subsequent type-I interferon response, and meanwhile lowers ZEB1 levels to further unleash the expression of interferon simulated genes. In turn, we demonstrate that DOT1L loss or treatment with the selective DOT1L inhibitor EPZ-5676 sensitizes tumors to immune checkpoint blockade by increased immune infiltration in mouse. More importantly, EPZ-5676 treatment alone is sufficient to enhance antitumor immunity in humanized mouse model. These findings provide a rationale for targeting DOT1L to improve tumor immunogenicity and overcome immunotherapy resistance.

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Dual function of DOT1L suppresses tumor intrinsic immunogenicity in Hepatocellular carcinoma [ATAC-seq]

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Functional effect of DOT1L pharmacological inhibition in ERα-positive Ovarian Cancer cells

Project description:Estrogen Receptor alpha (ERα), a nuclear receptor with transcriptional activity, is a master regulator of estrogen signaling, widely known as therapeutic target in hormone-responsive breast cancer (BC). Moreover, ERα is highly expressed in approximately 80% of High Grade Serous Ovarian Cancer (HGSOC), the most common epithelial ovarian carcinoma. Despite some promising clinical trials evaluating endocrine therapy in this type of tumor, the role of ERα is still unknown. Epigenetic changes, such as DNA methylation, are emerging as key contributing factors to carcinogenesis. Disruptor of telomeric silencing-1-like (DOT1L), the only known histone methyl transferase capable to produce H3K79 mono, di and tri-methylation, modulates ERα actions in hormone-responsive BC. Considering this evidence, ERα-DOT1L association was confirmed in ERα-positive OC cells, PEO1 and PEO4, by Co-IP. DOT1L pharmacological inhibition by EPZ004777 (EPZ) revealed the involvement of this epigenetic enzyme in cell proliferation, cell cycle progression and apoptosis. Transcriptome profiling after ICI (a Selective Estrogen Receptor Degrader) and EPZ treatment, in both cell lines, has underlined a deep impact of both compounds on ERα-modulated genes, including the down-regulation of ERα itself. On the other hand, functional analysis showed that commonly affected transcripts are involved in different cellular processes, such as cancer cell survival, chemoresistance and cell cycle progression. Moreover, ChIP-qPCR performed on ERα promoter highlighted ERα and DOT1L co-localization, both in PEO1 and in PEO4 cells, which was reduced after EPZ treatment, suggesting a role of this complex on receptor transcriptional activity. In addition, drug combination studies performed with EPZ and ICI showed an additive effect in cell growth inhibition. Taken together, these results suggest DOT1L as a potential therapeutic target in the treatment of OC.

2019-11-04 | E-MTAB-8198 | biostudies-arrayexpress

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