Potent stimulation of the androgen receptor instigates a viral mimicry response in prostate cancer [ChIP-seq]
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PROVIDER: PRJNA777835 | ENA |
REPOSITORIES: ENA
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Project description:Potent stimulation of the androgen receptor instigates a viral mimicry response in prostate cancer
| PRJNA777544 | ENA
Project description:Potent stimulation of the androgen receptor instigates a viral mimicry response in prostate cancer [RNA-seq]
| PRJNA777549 | ENA
Project description:Inhibiting the androgen receptor (AR), a ligand-activated transcription factor, with androgen deprivation therapy is a standard-of-care treatment for metastatic prostate cancer (PCa). Paradoxically, activation of AR can also inhibit the growth of PCa in some patients and experimental systems, but the mechanisms underlying this phenomenon are poorly understood. This study exploited a potent synthetic androgen, methyltestosterone (MeT), to investigate AR agonist-induced growth inhibition. MeT strongly inhibited growth of PCa cells expressing AR, but not AR-negative models. Genes and pathways regulated by MeT were highly analogous to those regulated by DHT, although MeT induced a quantitatively greater androgenic response in PCa cells. MeT potently down-regulated DNA methyltransferases, leading to global DNA hypomethylation. These epigenomic changes were associated with dysregulation of transposable element expression, with long-term MeT treatment resulting in upregulation of endogenous retrovirus (ERV) transcripts. Increased ERV expression led to accumulation of double-stranded RNA and a “viral mimicry” response characterised by activation of interferon signalling, upregulation of MHC Class I molecules and enhanced recognition of murine PCa cells by CD8+ T cells. Positive associations between AR activity and ERVs/anti-viral pathways were evident in patient transcriptomic data, supporting the clinical relevance of our findings. Collectively, our study reveals that the potent androgen MeT can increase the immunogenicity of PCa cells via a viral mimicry response, a finding that has potential implications for the development of strategies to sensitize this cancer type to immunotherapies.
2022-02-01 | GSE188150 | GEO
Project description:Inhibiting the androgen receptor (AR), a ligand-activated transcription factor, with androgen deprivation therapy is a standard-of-care treatment for metastatic prostate cancer (PCa). Paradoxically, activation of AR can also inhibit the growth of PCa in some patients and experimental systems, but the mechanisms underlying this phenomenon are poorly understood. This study exploited a potent synthetic androgen, methyltestosterone (MeT), to investigate AR agonist-induced growth inhibition. MeT strongly inhibited growth of PCa cells expressing AR, but not AR-negative models. Genes and pathways regulated by MeT were highly analogous to those regulated by DHT, although MeT induced a quantitatively greater androgenic response in PCa cells. MeT potently down-regulated DNA methyltransferases, leading to global DNA hypomethylation. These epigenomic changes were associated with dysregulation of transposable element expression, with long-term MeT treatment resulting in upregulation of endogenous retrovirus (ERV) transcripts. Increased ERV expression led to accumulation of double-stranded RNA and a “viral mimicry” response characterised by activation of interferon signalling, upregulation of MHC Class I molecules and enhanced recognition of murine PCa cells by CD8+ T cells. Positive associations between AR activity and ERVs/anti-viral pathways were evident in patient transcriptomic data, supporting the clinical relevance of our findings. Collectively, our study reveals that the potent androgen MeT can increase the immunogenicity of PCa cells via a viral mimicry response, a finding that has potential implications for the development of strategies to sensitize this cancer type to immunotherapies.
2022-02-01 | GSE187413 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-02-01 | GSE187414 | GEO
Project description:Epigenetic therapies that alter DNA- and/or histone modifications facilitate transcription of immunogenic repetitive elements that cull cancer cells through ‘viral mimicry’ responses. Paradoxically, cancer-initiating events that include functional inactivation of canonical tumor suppressor proteins also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize patient-derived premalignant lesions of the fallopian tube along with syngeneic mouse models of epithelial ovarian cancer to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss disrupts constitutive heterochromatin to permit transcription of immunogenic repetitive elements capable of activating viral mimicry responses. While acute viral mimicry activation diminishes cell fitness, chronic viral mimicry activation following p53 loss promotes epigenetic reprogramming that increases tolerance of cytosolic nucleic acids and diminishes cellular immunogenicity as a pro-survival adaptation. This selection process we describe as ‘viral mimicry conditioning’ can be partially attenuated by the reverse transcriptase inhibitor 3TC to delay spontaneous tumorigenesis. Altogether, these results reveal that viral mimicry conditioning following p53 loss selects for diminished cell immunogenicity to promote immune evasion upon cancer initiation. Disruption of viral mimicry conditioning during cancer initiation may represent a pharmacological target for early cancer interception.
2024-03-26 | GSE216639 | GEO
Project description:The transcription factor and RNA-interacting Y-box binding protein-1 (YB-1 protein, YBX1 gene) has gained interest as a prognostic biomarker and therapeutic target in various malignancies including prostate cancer. Using a custom prostate-cancer-focussed microarray platform, we have established a transcriptome-wide profile of YB-1 target transcripts in the androgen sensitive prostate cancer cell line LNCaP, including RNAs regulated by YB-1 at the post-transcriptional level; under androgen deprived culture conditions and following stimulation with dihydrotestosterone (DHT).
2022-01-17 | GSE125338 | GEO
Project description:We performed H3K27ac ChIP-seq, ATAC-seq, and RNA-seq in LNCaP with and without androgen stimulation
2022-06-14 | GSE205885 | GEO
Project description:The TMPRSS2-ERG fusion positive prostate cancer cell line VCaP was grown for 72h in steroid depleted media (RPMI 10% CDT FBS) prior to vehicle (ethanol) or androgen stimulation (1nM R1881). To allow detailed analysis of androgen regulated gene expression in the VCaP prostate cancer cell line total RNA was harvested every every hour up to 24h using trizol (Sigma), quantified using a Nanodrop spectrophotometer (ND-1000). RNA samples were prepared for analysis on Illumina Human 12 v3 BeadArrays. Raw bead-summary data were generated using GenomeStudio version 1.9.0 (Illumina Inc.). For integrative analysis expression array data were normalised in R using the beadarray software and BASH (see Supplementary Methods for details) (Cairns et al., 2008; Dunning et al., 2007).
2014-12-31 | E-MTAB-2968 | biostudies-arrayexpress
Project description:Androgen receptor (AR) is expressed in 60-70% of breast cancers independent of estrogen receptor (ER) expression, however its function in breast cancer is largely unknown. Our study identified the high level of AR in ERâ??/HER2+ breast tumors and andorgen and AR greatly stimulated growth of MDA-MB-453 breast cancer cells. To define the genome-wide AR binding sites, we performed AR ChIP-seq using MDA-MB-453 breast cancer cells followig stimulation of DHT. We also identified FOXA1 is a crucial AR cofactor in MDA-MB-453 cells and the FOXA cistrome showed signaficant overlap with AR at both early and late time points of DHT stimulation. AR ChIP was performed in MDA-MB-453 breast cancer cells following 5a-dihydrotestosterone (DHT) stimulation for 4h and 16h respectively. FOXA1 ChIP-seq was performed after 4h DHT stimulation in MDA-MB-453 cells.
2011-07-11 | E-GEOD-28788 | biostudies-arrayexpress