Transcriptomic response of LSD1-UTX inhibitor on human breast cancer MCF7 cells
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ABSTRACT:
PROVIDER: PRJNA533785 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8931640_1.fastq.gz | Fastqsanger.gz | |||
| SRR8931640_2.fastq.gz | Fastqsanger.gz | |||
| SRR8931641_1.fastq.gz | Fastqsanger.gz | |||
| SRR8931641_2.fastq.gz | Fastqsanger.gz | |||
| SRR8931638_1.fastq.gz | Fastqsanger.gz |
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Project description:In many human cancers, including breast and prostate cancers, LSD1 and other lysine demethylases (KDMs), such as UTX, are co-expressed and co-localize with androgen receptors (AR) and estrogen receptors (ER), suggesting the potential use of hybrid molecules to target histone methylation and therefore to regulate/redirect hormone receptor signaling. Here, we report on the action of a pan-KDM inhibitor (3324), obtained by coupling the chemical properties of tranylcypromine, a known LSD1 inhibitor, with the 2OG competitive moiety developed for JmjC inhibition. The 3324 hybrid molecule displays unique features not exhibited by moieties and well-characterized single inhibitors. The compound efficiently inhibits LSD1 as well as UTX enzymes, inducing significant growth arrest and apoptosis in hormone-responsive cells accompanied by a robust increase in H3K4me2 and H3K27me3. Treatment with 3324 reduces the level of ERα in breast and AR in prostate cancer cells at both transcriptional and non-transcriptional levels, acting as a selective endocrine receptor disruptor (SERD). Treatment with 3324 alters the methylation status of ER-regulated promoter regions, thereby affecting the transcription of genes involved in cell surveillance, death, and immune response. 3324 reduces cell proliferation in ex vivo breast cancers by interfering with hormone receptor signaling and/or receptor stability, as well as in cell models with acquired resistance to endocrine therapies (BT474, C4-2 and C4-2b). Similarly, 3324 displays tumor-selective potential in vivo, in both xenograft and chicken embryo models, with no toxicity and good oral efficacy. This multi-target approach may overcome potential mechanism(s) of resistance caused in part by redundancy and robustness of biological pathways, and find potential application in the treatment of resistant-to-therapy cancers such as those with acquired tamoxifen/enzalutamide resistance.
2020-10-15 | GSE130067 | GEO
Project description:Lysine specific demethylase 1 (LSD1) is an important histone demethylase that mediates metastasis in luminal breast cancer. Thus, the characterization of miRNAs in MCF7 cells regulated by LSD1 is imperative in clarifying intercellular signaling.
2024-03-04 | GSE218200 | GEO
Project description:Lysine specific demethylase 1 (LSD1) is an important histone demethylase that mediates metastasis in luminal breast cancer. Exosomes play a major role in cell-to-cell communication. Thus, the characterization of miRNAs of exosome in MCF7 cells regulated by LSD1 is imperative in clarifying intercellular signaling.
2024-03-04 | GSE212291 | GEO
Project description:Metastasis accounts for almost 90% of breast cancer-related fatalities, making it frequent malignancy and the main reason of tumor mortality globally among women. A key player in breast cancer is the histone demethylase lysine-specific demethylase 1 (LSD1). We used LSD1 knockdown MCF7 and T47D cell exosomes to treat breast cancer cells for greatly increasing the invasion and migration of breast cancer cells for evaluating the impact of LSD1 on breast cancer invasion and migration. miR-1290 expression was downregulated in LSD1 knockdown MCF7 exosomes. Furthermore, miR-1290 could control NAT1 expression by looking through the database of miR-1290 target genes. These data provide fresh insights into the biology of breast cancer therapy by demonstrating how the epigenetic factor LSD1 stimulates the breast cancer cells’ invasion and migration via controlling exosomal miRNA.
2024-07-31 | GSE266982 | GEO
Project description:Expression profile of MCF7 and T47D human breast cancer cell lines upon treatment with the BET bromodomian inhibitor JQ1
2017-05-08 | GSE95287 | GEO
Project description:The role of histone lysine methylation in estrogen receptor-alpha (ERα)-activated transcription is highly context-specific and poorly understood. Here, we show that lysine demethylase 1 (LSD1) mediates loss of H3 lysine 4 dimethylation (H3K4me2) in coordination with tripartite-motif-containing protein 24 (TRIM24)- regulated growth of breaset cancer-derived cells. We performed global profiling of histone H3K4me2 in comparison to genome-wide binding of TRIM24 in MCF7 cells when estrogen is depleted or added. We found specific subsets of genes with functions in transcription and cell proliferation are depleted of H3K4me2 at TRIM24 binding sites. Chromatin immunoprecipitation (ChIP) analyses over a time course of estrogen induction revealed cyclic demethylation of H3K4me2, LSD1, TRIM24 and ERα binding. Inhibition of LSD1 enzymatic activity led to increased H3K4me2 and decreased estrogen response of TRIM24-dependent genes. Additon of a small molecule inhibitor of the TRIM24 bromodomain or depletion of TRIM24 expression amplified the impact of LSD1 inhbition as measured by survival and proliferation of MCF7 cells, suggesting that combinatorial inhibition of LSD1 and TRIM24 may be effective in targeting ER-positive breast cancers.
2019-12-01 | GSE113654 | GEO
Project description:Background: Epithelial to mesenchymal transition (EMT) plays an essential role in the metastasis of breast cancer by regulating the migration and invasion of cancer cells. Lysine specific demethylase 1 (LSD1) is an important histone demethylase that mediates EMT. However, the functional effects of the mutation on LSD1 in breast cancer remain unclear. Results: An E239K mutation of LSD1 was identified from TCGA Breast Invasive Carcinoma cohort. To investigate the functional effects of the E239K mutation of LSD1, a stable LSD1 knockdown MCF7 cell line was generated. Rescue with the wild-type LSD1, but not the E239K mutated LSD1, suppressed the increased invasion of the LSD1 knockdown cells, demonstrating that the E239K mutation abolished the suppressive effects of LSD1 on the invasion of breast cancer cells. Further analysis showed that the E239K mutation of LSD1 led to decreased expression of estrogen receptor α (ERα), which subsequently increased the expression of Slug, a master transcription factor that promoted EMT. Most importantly, the E239K mutation of LSD1 disrupted the interaction between LSD1 and GATA3, which reduced the enrichment of LSD1 at the promoter region of ERα gene. The reduced enrichment of LSD1 at the promoter region of ERα gene caused enhanced histone H3K9 methylation, which in turn suppressed the transcription of ERα gene. Conclusions: The E239K mutation of LSD1 promotes the migration and invasion of breast cancer cells by disrupting the interaction between LSD1 and GATA3, which reduces the expression of ERα by enhancing the histone H3K9 methylation.
2021-03-12 | GSE168706 | GEO
Project description:Lysine-specific demethylase 1 (LSD1), a histone demethylating enzyme, plays a crucial role in cancer metastasis. While studies have demonstrated that the knockout of LSD1 significantly enhances lung metastasis of breast cancer cells, it remains unclear whether LSD1-deficient breast cancer cells can remodel the lung microenvironment to allow metastasis. In this study, we isolated exosomes from LSD1-knockdown breast cancer cells (LSD1 KD) and investigated their effects on the formation of pre-metastatic niches. The intravenous injection of exosomes from LSD1 KD cells in mice resulted in a substantial increase in lung colonization by breast cancer cells, while treatment with exosomes derived from LSD1 KD cells decreased the expression of the tight junction proteins ZO-1 and occludin in vascular endothelial cells, leading to increased pulmonary vascular permeability. In addition, the knockdown of LSD1 reduced the expression of the circular RNA circDOCK1, which augmented the levels of miR-1270 in exosomes. Further investigation showed that miR-1270 inhibited ZO-1 expression in human umbilical vein endothelial cells, which enhanced their permeability. In conclusion, our study uncovered a novel mechanism in which the epigenetic modifier LSD1 promotes the formation of pre-metastatic niches via the regulation of exosomal miRNA.
2024-09-12 | GSE264699 | GEO
Project description:Lysine-specific demethylase 1 (LSD1), a histone demethylating enzyme, plays a crucial role in cancer metastasis. While studies have demonstrated that the knockout of LSD1 significantly enhances lung metastasis of breast cancer cells, it remains unclear whether LSD1-deficient breast cancer cells can remodel the lung microenvironment to allow metastasis. In this study, we isolated exosomes from LSD1-knockdown breast cancer cells (LSD1 KD) and investigated their effects on the formation of pre-metastatic niches. The intravenous injection of exosomes from LSD1 KD cells in mice resulted in a substantial increase in lung colonization by breast cancer cells, while treatment with exosomes derived from LSD1 KD cells decreased the expression of the tight junction proteins ZO-1 and occludin in vascular endothelial cells, leading to increased pulmonary vascular permeability. In addition, the knockdown of LSD1 reduced the expression of the circular RNA circDOCK1, which augmented the levels of miR-1270 in exosomes. Further investigation showed that miR-1270 inhibited ZO-1 expression in human umbilical vein endothelial cells, which enhanced their permeability. In conclusion, our study uncovered a novel mechanism in which the epigenetic modifier LSD1 promotes the formation of pre-metastatic niches via the regulation of exosomal miRNA.
2024-09-12 | GSE264698 | GEO
Project description:Complex regulatory networks control epithelial-to-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs. LSD1 phosphorylation at serine-111 (LSD1-s111p) by chromatin anchored protein kinase C-theta (PKC-θ), is critical for its demethylase and EMT promoting activity and LSD1-s111p is enriched in chemoresistant cells in vivo. LSD1 couples to PKC-θ on the mesenchymal gene epigenetic template promotes LSD1-mediated gene induction. In vivo, chemotherapy reduced tumour volume, and when combined with an LSD1 inhibitor, abrogated the mesenchymal signature and promoted an innate, M1 macrophage-like tumouricidal immune response. Circulating tumour cells (CTCs) from metastatic breast cancer (MBC) patients were enriched with LSD1 and pharmacological blockade of LSD1 suppressed the mesenchymal and stem-like signature in these patient-derived CTCs. Overall, LSD1 inhibition may serve as a promising epigenetic adjuvant therapy to subvert its pleiotropic roles in breast cancer progression and treatment resistance.
2018-01-11 | GSE104754 | GEO