Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA262163 | ENA |
REPOSITORIES: ENA
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Project description:While tissue and lineage-specific super-enhancers (SEs) regulate cell fate decision during development, the nature of Castration Resistant Prostate Cancer (CRPC)-specific SEs (CSEs) is unknown. Herein we report the lysine 13 (K13) acetylation of HOXB13 mediated by the histone acetyltransferase CBP/p300 regulates prostate tumor autonomy. The acK13-HOXB13 shadows H3K27ac at lineage specific SEs and surpasses it at CSEs. In contrast, mutation of HOXB13 at K13 sensitizes CRPCs to Enzalutamide, disables spheroid and xenograft tumor formation. Mechanistically, the acK13-HOXB13 interacts with chromatin remodeling bromodomain proteins to regulate tumor-specific CSE selection. These CSEs sprout at critical lineage genes NKX3-1, Androgen receptor (AR), AR regulator ACK1 tyrosine kinase and tyrosine kinase ligands regulating angiogenesis. Single-cell transcriptomic analysis of human prostate tumor organoids reveal ACK1 expression underlies sensitivity to the small molecule inhibitor (R)-9b over AR-targeted agents. Collectively, our studies reveal acK13-HOXB13 regulated epigenome as a key cog in prostate cancer cell autonomy.
2022-09-22 | GSE167506 | GEO
Project description:While tissue and lineage-specific super-enhancers (SEs) regulate cell fate decision during development, the nature of Castration Resistant Prostate Cancer (CRPC)-specific SEs (CSEs) that drive resistance to AR-targeted therapies is unknown. Herein we report the lysine 13 (K13)-acetylation of Homeodomain transcription factor HOXB13 as a critical feature underlying CSE exclusivity. The histone acetyltransferase (HAT) CBP/p300 specifically acetylates HOXB13 (acK13-HOXB13) in prostate cancer cells. The acK13-HOXB13 enriched CSEs sprout at critical lineage genes such as the NKX3-1, Androgen receptor (AR), AR regulator ACK1/TNK2 a tyrosine-kinase and tyrosine kinase ligands associated with angiogenesis, including VEGFA and ANGPT2/ANGPTL3 to expedite prostate tumor autonomy.
2022-09-22 | GSE169133 | GEO
Project description:TMPRSS2 is an androgen-regulated cell surface serine protease expressed predominantly in prostate epithelium. TMPRSS2 is expressed highly in localized high-grade prostate cancers and in the majority of human prostate cancer metastasis. Through the generation of mouse models with a targeted deletion of Tmprss2, we demonstrate that the activity of this protease regulates cancer cell invasion and metastasis to distant organs. By screening combinatorial peptide libraries we identified a spectrum of TMPRSS2 substrates that include pro-hepatocyte growth factor (HGF). HGF activated by TMPRSS2 promoted c-Met receptor tyrosine kinase signaling, and initiated a pro-invasive EMT phenotype. Chemical library screens identified a potent bioavailable TMPRSS2 inhibitor that suppressed prostate cancer metastasis in vivo. Together, these findings provide a mechanistic link between androgen-regulated signaling programs and prostate cancer metastasis that operate via context-dependent interactions with extracellular constituents of the tumor microenvironment. Custom mouse cDNA microarrays were used to measure transcript levels in microdissected anterior prostate tumors from Tmprss2+/+;TRAMP mice, Tmprss2-/-;TRAMP mice or strain-matched benign epithelium. All samples were laser-capture microdissected and total RNA isolated and amplified prior to hybridization against a reference pool of normal adult mouse tissues.
2014-09-09 | E-GEOD-58822 | biostudies-arrayexpress
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2014-09-27 | GSE61800 | GEO
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2022-12-09 | GSE216628 | GEO
Project description:Treatment of prostate cancer cell lines with Androgen Receptor and Receptor Tyrosine Kinase inhibitors
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Project description:TMPRSS2 is an androgen-regulated cell surface serine protease expressed predominantly in prostate epithelium. TMPRSS2 is expressed highly in localized high-grade prostate cancers and in the majority of human prostate cancer metastasis. Through the generation of mouse models with a targeted deletion of Tmprss2, we demonstrate that the activity of this protease regulates cancer cell invasion and metastasis to distant organs. By screening combinatorial peptide libraries we identified a spectrum of TMPRSS2 substrates that include pro-hepatocyte growth factor (HGF). HGF activated by TMPRSS2 promoted c-Met receptor tyrosine kinase signaling, and initiated a pro-invasive EMT phenotype. Chemical library screens identified a potent bioavailable TMPRSS2 inhibitor that suppressed prostate cancer metastasis in vivo. Together, these findings provide a mechanistic link between androgen-regulated signaling programs and prostate cancer metastasis that operate via context-dependent interactions with extracellular constituents of the tumor microenvironment.
2014-09-09 | GSE58822 | GEO
Project description:Extracellular matrix (ECM) regulates carcinogenesis. As a major ECM component, collagen interacts with integrin and a non-typical receptor discoidin domain receptor tyrosine kinase 2 (DDR2), but how DDR2 regulates cancer progression is poorly understood. Apart from its signaling function, ECM provides a mechanical environment for cancer, but the impact of biomechanics on cancer remains enigmatic. Here, we performed RNA-seq of a human neuroblastoma cell line SH-SY5Y. We found that DDR2 knockdown, but not increasing substrate stiffness, upregulated pro-proliferative genes and down-regulated axonogenesis genes. Surprisingly, despite no transcriptome changes, increasing of stiffness attenuates SH-SY5Y cell proliferation, an effect also observed after DDR2 knockdown. Our results indicate that two ECM effectors, DDR2 and biomechanics, could control cancer cell proliferation through different mechanisms.
2024-04-19 | GSE246550 | GEO
Project description:Knockdown of the receptor tyrosine kinase EphB4 using siRNA in LNCaP prostate cancer cells compared to negative siRNA controls In this study there were four replicates of EphB4 siRNA treated samples and three replicates of negative non-silencing siRNA controls
2014-09-27 | E-GEOD-61800 | biostudies-arrayexpress