Project description:The aim of this study is to identify the LSD1 target genes in metastatic androgen independent prostate cancer Lysine-specific demethylase 1 (LSD1) was shown to control gene expression and cell proliferation of androgen-dependent prostate cancer (PCa) cells, whereas the role of LSD1 in androgen-independent metastatic prostate cancer remains elusive. Here, we show that depletion of LSD1 leads to increased migration and invasion of androgen-independent PCa cells. Transcriptome and cistrome analyses reveal that LSD1 regulates expression of lysophosphatidic acid receptor 6 (LPAR6) and cytoskeletal genes including the focal adhesion adaptor protein paxillin (PXN). Enhanced LPAR6 signalling upon LSD1 depletion promotes migration with concomitant phosphorylation of PXN. In mice LPAR6 overexpression enhances, whereas knockdown of LPAR6 abolishes metastasis of androgen-independent PCa cells. Taken together, we uncover a novel mechanism of how LSD1 controls metastasis and identify LPAR6 as a promising therapeutic target to treat metastatic prostate cancer.
Project description:The aim of this study is to identify the LSD1 target genes in metastatic androgen independent prostate cancer Lysine-specific demethylase 1 (LSD1) was shown to control gene expression and cell proliferation of androgen-dependent prostate cancer (PCa) cells, whereas the role of LSD1 in androgen-independent metastatic prostate cancer remains elusive. Here, we show that depletion of LSD1 leads to increased migration and invasion of androgen-independent PCa cells. Transcriptome and cistrome analyses reveal that LSD1 regulates expression of lysophosphatidic acid receptor 6 (LPAR6) and cytoskeletal genes including the focal adhesion adaptor protein paxillin (PXN). Enhanced LPAR6 signalling upon LSD1 depletion promotes migration with concomitant phosphorylation of PXN. In mice LPAR6 overexpression enhances, whereas knockdown of LPAR6 abolishes metastasis of androgen-independent PCa cells. Taken together, we uncover a novel mechanism of how LSD1 controls metastasis and identify LPAR6 as a promising therapeutic target to treat metastatic prostate cancer.
Project description:The main objective of the current study is to determine, using transcriptomic analysis on patient derived-xenograft models, whether differentially aggressive PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern. Transcriptomic profiling (RNA Sequencing) was performed on PCa PDX models representing different disease stages; BM18 (androgen dependent bone metastasis) and LAPC9 (androgen independent bone metastasis).
Project description:The lysine demethylase 3A (KDM3A, JMJD1A or JHDM2A) controls transcriptional networks in a variety of biological processes such as spermatogenesis, metabolism, stem cell activity and tumor progression. We matched transcriptomic and ChIP-Seq profiles to decipher a genome-wide regulatory network of epigenetic control by KDM3A in prostate cancer cells. ChIP-Seq experiments monitoring histone 3 lysine 9 (H3K9) methylation marks show global histone demethylation effects of KDM3A. Combined assessment of histone demethylation events and gene expression changes presented major transcriptional activation suggesting that distinct oncogenic regulators may synergize with the epigenetic patterns by KDM3A. Pathway enrichment analysis of cells with KDM3A knockdown prioritized androgen signaling indicating that KDM3A plays a key role in regulating androgen receptor activity. Matched ChIP-Seq and knockdown experiments of KDM3A in combination with ChIP-Seq of the androgen receptor resulted in a gain of H3K9 methylation marks around androgen receptor binding sites of selected transcriptional targets in androgen signaling including positive regulation of KRT19, NKX3-1, KLK3, NDRG1, MAF, CREB3L4, MYC, INPP4B, PTK2B, MAPK1, MAP2K1, IGF1, E2F1, HSP90AA1, HIF1A, and ACSL3. The cancer systems biology analysis of KDM3A-dependent genes identifies an epigenetic and transcriptional network in androgen response, hypoxia, glycolysis, and lipid metabolism. Genome-wide ChIP-Seq data highlights specific gene targets and the ability of KDM3A to control oncogenic pathways in prostate cancer cells.
Project description:Epithelial-to-mesenchymal transition (EMT) and cancer stem cells play relevant roles in metastasis and drug resistance in castration-resistant PCa. Conditioned-media from Cancer-Associated Fibroblasts from two patients with aggressive PCa induce EMT, reversible DNA methylation and transcriptional variations in androgen independent PC3, but not in androgen dependent LN-CaP cells. Focal CpG islands hyper-methylation associated to transcriptional repression of epithelial markers occurs together with widespread hypo-methylation, including promoters of EMT and stemness regulating genes resulting in their transcriptional activation. Remarkably, DNA methylation and transcription patterns are entirely reverted upon exposure to serum-free medium (mesenchymal-to-epithelial transition). DNMT3A is required for de novo methylation and silencing of CDH1 and GRHL2, the ZEB1 direct repressor, while its knock-down prevents EMT entry. These unprecedented results highlight that CAF-released factors induce reversible DNA methylation patterns required for transcriptional variations essential for EMT and stemness in androgen independent PCa cells, suggesting that similar plasticity might occur in tumour microenvironment.
Project description:Androgen Receptor Gene Expression in Prostate Cancer is Directly Suppressed by the Androgen Receptor Through Recruitment of Lysine Specific Demethylase 1