In vitro cell-line model to evaluate oncogenic functions associated with the HOXB13 protein with X285K variant
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ABSTRACT:
PROVIDER: PRJNA1003441 | ENA |
REPOSITORIES: ENA
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Project description:A few recent reports uncovered a HOXB13 variant (X285K) predisposing to prostate cancer in men of West-African ancestry. The protein function associated with this inherited variant is unknown. To elucidate the oncogenic mechanisms of the X285K protein, we designed an in vitro cell-line model to evaluate oncogenic functions associated with the X285K protein. Replacement of the wild-type HOXB13 protein with the X285K protein resulted in a gain of the E2F/MYC signature, validated by a gain in the expression of Cyclin B1 and c-MYC, without affecting the androgen response signature. In conclusion, Functional studies revealed a unique gain-of-function oncogenic mechanism of X285K protein in regulating E2F/MYC signatures.
2023-10-06 | GSE240364 | GEO
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:HOXB13 is a homeodomain transcription factor with prostate-specific expression. It is essential for normal prostate epithelium differentiation during development and functions as a key regulator of androgen-dependent cell growth in adult and cancerous prostate. Previous studies have demonstrated that HOXB13 is a pioneer factor of the androgen receptor (AR) and also a critical cofactor of AR variant v7 in castration-resistant prostate cancer (PCa). However, the intrinsic function of HOXB13 as a DNA-binding protein in an AR-independent context has not been elucidated. Here, our data reveal HOXB13, but not G84E mutant, recruits HDAC3 to specific genomic regions to catalyze histone de-acetylation and chromatin remodeling. We demonstrate a predominant function of HOXB13 in transcriptional repression of lipogenic genes requiring HDAC3.
2022-04-01 | GSE153585 | GEO
Project description:HOXB13 is a homeodomain transcription factor with prostate-specific expression. It is essential for normal prostate epithelium differentiation during development and functions as a key regulator of androgen-dependent cell growth in adult and cancerous prostate. Previous studies have demonstrated that HOXB13 is a pioneer factor of the androgen receptor (AR) and also a critical cofactor of AR variant v7 in castration-resistant prostate cancer (PCa). However, the intrinsic function of HOXB13 as a DNA-binding protein in an AR-independent context has not been elucidated. Here, our data reveal HOXB13, but not G84E mutant, recruits HDAC3 to specific genomic regions to catalyze histone de-acetylation and chromatin remodeling. We demonstrate a predominant function of HOXB13 in transcriptional repression of lipogenic genes requiring HDAC3.
2022-04-01 | GSE153583 | GEO
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: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:HOXB13 is a developmentally regulated transcription factor, co-expressed along with the Androgen receptor (AR) in a majority of PCs. Previous studies have indicated context dependent roles of HOXB13 in the functional regulation of AR and enrichment of HOXB13 motifs in the AR cistrome. Our studies showed that genetic or pharmacological blockade of HOXB13 sensitized mCRPCs to Enzalutamide (ENZ, Xtandi), an anti-androgen that is currently deployed to treat mCRPC patients. To identify HOXB13-mediated mechanism of castration-resistance ChIP-sequencing was performed with the HOXB13-K13ac, or IgG antibodies in the metastatic prostate cancer cell line, C4-2B in vehicle treated as well as Enzalutamide treated cell lines. We demonstrated for the first time that BRD4, epigenetically regulates HOXB13 gene expression in PCs. Consistently, JQ1 the prototype BET inhibitor suppresses HOXB13 expression and inhibit mCRPC growth. ChIP-sequence analysis reveals that HOXB13 recruitment to the chromatin is not completely abrogated in Enzalutamide treated cells identify a subset of genes that may have potential role in CRPC proliferation, anti-androgen resistance and metastasis.
2022-01-30 | GSE125902 | 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:To understand the mechanistic role of HOXB13 lysine acetylation in CRPC development andd progression, differential gene expression analysis was performed following RNA-sequencing of the HOXB13K13A mutant versus the isogenic parental C4-2B to identify bonafide transcriptional targets of acetylated HOXB13. Chromatin remodeling and self-renewal genes were significantly impacted as a result of HOXB13-K13 mutation. These results suggested that single-site acetylation in HOXB13 is critical and may even be sufficient to promote cellular reprogramming associated with PC pathogenesis.
2022-09-22 | GSE174923 | GEO
Project description:We report the ChIP-seq analysis of HOXB13, H3K27Ac, H3K27me3, H3K4me3, and RNA POL II in G401 rhabdoid tumor of the kidney cells.
2017-01-30 | GSE65381 | GEO