HOXB13, HOXA11 and HOXA11-AS transcriptome regulation in prostate cancer cells
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ABSTRACT:
PROVIDER: PRJNA616229 | ENA |
REPOSITORIES: ENA
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Project description:Long noncoding RNAs (lncRNAs) are emerging as critical regulators of gene expression, playing fundamental roles in cancer development. We analyzed changes in transcriptome profiling in prostate cancer PC-3 cells transfected with siRNAs targeting lncRNA HOXA11-AS, its upstream regulator HOXB13 and its opposite strand protein coding gene HOXA11.
2021-01-24 | GSE147710 | GEO
Project description:Treatment induced-resistance of CRPC is an imminent undesirable outcome in patients. Tissue and lineage-specific super-enhancers (SEs) determine cell fate and plasticity during development and disease respectively. However, the identity and function of CRPC-specific SEs (CSEs) regulated genes is unknown. Herein we report the lysine 13 acetylation of the prostate-enriched transcription factor HOXB13 (acK13-HOXB13) mediated by the histone acetyl transferase (HAT) CBP/p300 as a critical mechanism of CSE establishment. Mechanistically, acK13-HOXB13 establishes the CRPC enhanceosome comprising chromatin remodeling bromo-domain proteins SMARCA2/BAZ2B and the HAT p300/CBP which enable histone and non-histone protein acetylation at CSEs. Such CSEs sprout at tyrosine kinase genes encoding ACK1/TNK2, VEGFA, and ANGPT2/ANGPTL3 to increase pathogenic output in primary human tumors. These tyrosine kinase mediated signaling cascades establish robust networks to conduce growth, survival and androgen-bypass. Consistently, the loss of function acK13-HOXB13 mutants show significant reduction of proliferation, spheroid formation, and xenograft tumor growth that correlates with the high sensitivity to the AR-antagonist Enzalutamide. Targeting HOXB13 acetylation mediated CRPC-SE establishment at critical tyrosine kinase genes could therefore have significant clinical implications in preventing PC recurrence.
2022-09-22 | GSE169132 | GEO
Project description:HOXB13 epigenome in castration-resistant prostate cancer
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Project description:Dysregulation of mTOR signaling plays a critical role in promoting prostate cancer (PCa) growth. HOXB13, a homeodomain transcription factor, is known to influence the androgen response and PCa development. Recently, HOXB13 was found to complex with mTOR on chromatin. However, the functional crosstalk between HOXB13 and mTOR remains elusive. We now report that mTOR directly interacts with and hierarchically phosphorylates HOXB13 at threonine 8 and 41 then serine 31 to promote its destabilization by the E3 ligase SKP2 while enhancing its oncogenic properties. Expression of HOXB13 harboring phosphomimetic mutations at the mTOR-targeted sites stimulates PCa cellular growth both in vitro and in murine xenografts. Transcriptional profiling studies revealed a phospho-HOXB13-dependent gene signature capable of robustly discriminating between normal prostate tissues, primary and metastatic PCa samples. This work uncovers a previously unanticipated molecular cascade by which mTOR directly phosphorylates HOXB13 to dictate a specific gene program with oncogenic implications in PCa.
2023-07-19 | GSE225206 | GEO
Project description:To identify potential cofactors of HOXB13 in suppressing lipogenic programs in prostate cancer cells, we performed tandem affinity purification followed by mass spectrometry analysis of WT and G84E HOXB13 expressed in LNCaP cells. Out of the HOXB13-enriched proteins are previously reported interactors such as AR and its cofactors FOXA1, GATA2, and NKX3. However, these interactions were not disrupted by G84E as compared to WT HOXB13. Interestingly, we found strong interactions of HOXB13 with HDAC1/3 and their corepressors NCoR1/2 and TBL1X. Notably, these interactions were drastically reduced by G84E mutation.
2023-03-11 | PXD030810 | Pride
Project description:The constitutively active androgen receptor (AR) splice variant 7 (AR-V7) plays an important role in the progression of castration-resistant prostate cancer (CRPC). Although biomarker studies established the role of AR-V7 in resistance to AR-targeting therapies, how AR-V7 mediates genomic functions in CRPC remains largely unknown. Using a ChIP-exo approach, we show AR-V7 binds to distinct genomic regions and recognizes a full-length androgen-responsive element in CRPC cells and patient tissues. Remarkably, we find dramatic differences in AR-V7 cistromes across diverse CRPC cells and patient tissues, regulating different target gene sets involved in CRPC progression. Surprisingly, we discover that HoxB13 is universally required for and colocalizes with AR-V7 binding to open chromatin across CRPC genomes. HoxB13 pioneers AR-V7 binding through direct physical interaction, and collaborates with AR-V7 to up-regulate target oncogenes. Transcriptional coregulation by HoxB13 and AR-V7 was further supported by their coexpression in tumors and circulating tumor cells from CRPC patients. Importantly, HoxB13 silencing significantly decreases CRPC growth through inhibition of AR-V7 oncogenic function. These results identify HoxB13 as a pivotal upstream regulator of AR-V7-driven transcriptomes that are often cell context-dependent in CRPC, suggesting that HoxB13 may serve as a therapeutic target for AR-V7-driven prostate tumors.
2018-05-31 | GSE99378 | 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:HOXB13 is a prostate-specific homeodomain transcription factor that is mainly known as an androgen receptor (AR) cofactor. Recent studies have revealed AR-independent roles of HOXB13 in recruiting HDAC3 to suppress lipogenic programs in prostate cancer (PCa). As such, HOXB13 down-regulation leads to lipid accumulation and tumor metastasis, the molecular mechanisms of which, however, are incompletely understood. Here, we demonstrate that p300/CBP co-occupies HOXB13/HDAC3-repressed lipogenic enhancers and is required for their activation and target gene expression upon HOXB13 loss. We found that HOXB13 is down-regulated in metastatic hormone-sensitive PCa compared to their matched primary prostate tumors. HOXB13 loss induces matrix metalloproteinases (MMPs), which mediate HOXB13-depleted cell motility. Critically, CCS1477, a pharmacological inhibitor of p300/CBP, abolished HOXB13-loss-induced lipid accumulation, MMP gene expression, cell motility in vitro, and tumor metastasis in vivo. Taken together, our results suggest HOXB13 as a significant metastasis suppressor and identify p300/CBP as critical therapeutic targets in HOXB13-low metastatic PCa.
2025-10-08 | GSE296237 | GEO
Project description:HOXB13 is a prostate-specific homeodomain transcription factor that is mainly known as an androgen receptor (AR) cofactor. Recent studies have revealed AR-independent roles of HOXB13 in recruiting HDAC3 to suppress lipogenic programs in prostate cancer (PCa). As such, HOXB13 down-regulation leads to lipid accumulation and tumor metastasis, the molecular mechanisms of which, however, are incompletely understood. Here, we demonstrate that p300/CBP co-occupies HOXB13/HDAC3-repressed lipogenic enhancers and is required for their activation and target gene expression upon HOXB13 loss. We found that HOXB13 is down-regulated in metastatic hormone-sensitive PCa compared to their matched primary prostate tumors. HOXB13 loss induces matrix metalloproteinases (MMPs), which mediate HOXB13-depleted cell motility. Critically, CCS1477, a pharmacological inhibitor of p300/CBP, abolished HOXB13-loss-induced lipid accumulation, MMP gene expression, cell motility in vitro, and tumor metastasis in vivo. Taken together, our results suggest HOXB13 as a significant metastasis suppressor and identify p300/CBP as critical therapeutic targets in HOXB13-low metastatic PCa.
2025-10-08 | GSE296236 | 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) 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