LSD1 promotes castration-resistant prostate cancer progression
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Armand Bankhead
PROVIDER: E-GEOD-77763 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:LSD1 (also known as KDM1A) is a histone demethylase and a key regulator of gene expression in embryonic stem cells and cancer. LSD1 was initially identified as a transcriptional repressor via its demethylation of active histone H3 marks (di-methyl lysine 4 [2MK4]). In prostate cancer, specifically, LSD1 also co-localizes with the AR and demethylates repressive 2MK9 histone marks from androgen-responsive AR target genes, facilitating androgen-mediated induction of AR-regulated gene expression and androgen-induced proliferation in androgen-dependent cancers. Recently, it was shown that treatment with high doses of androgens (e.g.10-fold higher doses than those required for induction of expression of androgen-activated genes such as PSA) recruits LSD1 and AR to an enhancer within the AR; this AR and LSD1 recruitment represses AR transcription. Thus, LSD1 appears to play a role in mediating both the proliferative and repressive phases of the biphasic androgen dose-response curve. For these reasons, we hypothesized that LSD1 might be important for maintenance of AR signalling in castration-resistant prostate cancer (CRPC) tumors. However, in this report, we describe a distinct role of LSD1 as a driver of proliferation and survival of prostate cancer cells, including CRPC cells, irrespective of androgens or even AR expression. Specifically, LSD1 activates expression of cell cycle, mitosis, and embryonic stem cell maintenance pathways that are enriched in lethal prostate cancers - pathways not activated by androgens. Finally, we observe that treatment with a new LSD1 inhibitor potently and specifically suppresses LSD1 function and suppresses CRPC growth and survival in vitro and in vivo. Our data place LSD1 as a key driver of androgen-independent survival in lethal prostate cancers and demonstrate the potential of LSD1-directed therapies in the near-term. The enclosed files are from microarrays experiments after suppressing LSD1 with RNAi or stimulating cells with the androgen agonist dihydrotestosterone (DHT).
2016-06-30 | E-GEOD-61630 | biostudies-arrayexpress
Project description:LSD1 (also known as KDM1A) is a histone demethylase and a key regulator of gene expression in embryonic stem cells and cancer.1,2 LSD1 was initially identified as a transcriptional repressor via its demethylation of active histone H3 marks (di-methyl lysine 4 [2MK4]).1 In prostate cancer, specifically, LSD1 also co-localizes with the AR and demethylates repressive 2MK9 histone marks from androgen-responsive AR target genes, facilitating androgen-mediated induction of AR-regulated gene expression and androgen-induced proliferation in androgen-dependent cancers. We report here that the LSD1 protein is universally upregulated in human CRPC and promotes survival of CRPC cell lines. This effect is explained in part by LSD1-induced activation of cell cycle and embryonic stem cell gene setsâgene sets enriched in transcriptomal studies of lethal human tumors. Importantly, despite the fact that many of these genes are direct LSD1 targets, we did not observe histone methylation changes at the LSD1-bound regions, demonstrating non-canonical histone demethylation-independent mechanisms of gene regulation. This ChIP-seq dataset included H3K4me2 and H3K9me2 ChIP-seq data for siRNA target against LSD1 and non-targeting control, as well as SP2509 inhibition of LSD1 and mock treatment 4 conditions: siRNA against LSD1, siRNA against luciferase (non-targeting control); SP2509 inhibition of LSD1, mock treatment. There are 2 replicates per condition.
2016-06-30 | E-GEOD-77762 | biostudies-arrayexpress
Project description:dose and time dependent responses of dihydrotestosterone in androgen receptor over-expressing prostate cancer cells.
2009-10-09 | E-MEXP-2286 | biostudies-arrayexpress
Project description:We report that p53 knockdown changed AR-DNA binding across the genome. We found fewer AR-binding sites in the absence of p53. Examination of AR-DNA binding after p53 knockdown in LNCaP cells
2012-07-31 | E-GEOD-31294 | biostudies-arrayexpress
Project description:Prostate cancer is the commonest male cancer in Europe and the USA. The androgen receptor is a key transcription factor contributing to the development of all stages of the disease. In addition, other transcription factors have been associated with poor prognosis in prostate cancer, amongst which c-Myc is a well-established oncogene in many other cancers. We have previously reported that a role for the androgen receptor in prostate cancer is to promote glycolysis and anabolic metabolism. Many of these metabolic pathways are also c-Myc-regulated in other cancers. In this study we report that de novo purine biosynthesis is a c-Myc-dependent pathway in prostate cancer cells as determined by commensurate changes in the levels of enzymes in the pathway in response to siRNA knockdown of c-Myc and inducible overexpression of c-Myc. In addition c-Myc is recruited to the promoters of genes in the pathway as determined by chromatin immunoprecipitation. Using immunohistochemistry and real-time transcript detection we show that two enzymes (PAICS and IMPDH2) within the pathway are overexpressed in prostate cancers. An inhibitor of IMPDH2 reduces cell proliferation and significantly reduces the levels of guanosine triphosphate within treated cells. This imposes nucleolar stress on cells as determined by significant reductions in the levels of guanine nucleotide binding protein-like 3 (GNL3). In addition the levels of c-Myc, p53 and the androgen receptor are affected and the expression of tumour suppressive microRNA-34b is increased. Combining the IMPDH2 inhibitor with anti-androgens results in a combinatorial inhibition of cell proliferation. In conclusion we propose using enzymes within the de novo purine biosynthesis as cancer biomarkers and applying drugs to alter the flux through this pathway may represent an effective means of stratifying patients for therapy and sensitising some to AR-targeted therapies. Total RNA of three biological replicates for each condition was extracted using the RNeasy kit (Qiagen), conditions are: 5 h vehicle, 5 h Doxycycline, 12 h vehicle, 12 h Doxycyline
2016-03-17 | E-GEOD-51384 | biostudies-arrayexpress
Project description:Effect of dihydrotestosterone and castration on microRNA expression
2011-02-25 | E-MEXP-2602 | biostudies-arrayexpress
Project description:Following androgen ablation therapy (AAT), the vast majority of prostate cancer patients develop treatment resistance with a median time of 18-24 months to disease progression. To identify molecular targets that aid in prostate cancer cell survival and contribute to the androgen independent phenotype, we evaluated changes in LNCaP cell gene expression during 12 months of androgen deprivation. At time points reflecting critical growth and phenotypic changes, we performed Affymetrix expression array analysis to examine the effects of androgen deprivation during the acute response, during the period of apparent quiescence, and during the emergence of highly proliferative, androgen-independent prostate cancer cells (LNCaP-AI). We discovered alterations in gene expression for a host of molecules associated with promoting prostate cancer cell growth and survival, regulating cell cycle progression, apoptosis and adrenal androgen metabolism, in addition to AR co-regulators and markers of neuroendocrine disease. These findings illustrate the complexity and unpredictable nature of cancer cell biology and contribute greatly to our understanding of how prostate cancer cells likely survive AAT. The value of this longitudinal approach lies in the ability to examine gene expression changes throughout the cellular response to androgen deprivation; it provides a more dynamic illustration of those genes which contribute to disease progression in addition to specific genes which constitute a malignant androgen-independent phenotype. In conclusion, it is of great importance that we employ new approaches, such as the one proposed here, to continue exploring the cellular mechanisms of therapy resistance and identify promising targets to improve cancer therapeutics. Experiment Overall Design: To identify molecular targets that aid in prostate cancer cell survival and contribute to the androgen independent phenotype, we evaluated changes in LNCaP cell gene expression during 12 months of androgen deprivation. At time points reflecting critical growth and phenotypic changes, we performed Affymetrix expression array analysis to examine the effects of androgen deprivation during the acute response, during the period of apparent quiescence, and during the emergence of highly proliferative, androgen-independent prostate cancer cells (LNCaP-AI).
2008-04-07 | E-GEOD-8702 | biostudies-arrayexpress
Project description:Genome wide expression changes following treatment with the HDACs (Histone Deacetylase Inhibitor) CG-1521 (7.5uM) or TSA (Trichostatin A) were investigated to determine regulatory targets and patterns of the HDAC Inhibitors. LNCaP Prostate Cancer cells were treated for a period of 24h with either CG-1521 (7.5uM) or TSA (5uM) following a 24h seeding period. At the selected time point, total RNA was harvested from the cells for hybridization and analysis by Nimblgen Systems Inc using the homo sapiens gene expression array.
2007-09-15 | E-GEOD-8645 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-03-11 | E-GEOD-66852 | biostudies-arrayexpress
Project description:Genome wide expression changes following 50uM Casodex treatment were investigated to determine regulatory targets commonly overlooked in gene function specific microarrays and for comparison of the effects of the mutant androgen receptor (AR) LNCaP cell line against the wild-type AR expressing PC-346C cells. LNCaP Prostate Cancer cells were treated for a period of 48h with or without 50uM Casodex following a 24h seeding period. At the selected time point, total RNA was harvested from the cells for hybridization and analysis by Nimblgen Systems Inc using the homo sapiens gene expression array.
2007-09-15 | E-GEOD-8533 | biostudies-arrayexpress