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HOXB13 alters chromatin accessibility in prostate cancer through interactions with the SWI/SNF complex [ATAC-seq ]

ABSTRACT: Homeobox-B13 (HOXB13) is a master transcriptional regulator which is exclusively expressed in the prostate tissue and has been shown to be crucial for its embryonic development. There is extensive clinical and experimental evidence to support the role of HOXB13 in prostate cancer (PCa). Yet, despite this critical role, the function of HOXB13 remains controversial with some studies supporting an oncogenic role and others demonstrating a tumor-suppressive role. While there is a clear relationship between HOXB13 and AR there are conflicting studies if HOXB13 is itself regulated by AR. Interrogating various AR +ve and AR -ve in-vivo and in-vitro models, in this study, we demonstrate that HOXB13 is crucial for the growth and proliferation of PCa regardless of its androgen dependency. We show that HOXB13 activity in these different models is mediated via interactions with cell-specific transcription factors. Yet despite the diverse transcription factor interactions, HOXB13 activity is commonly modulated by SMARCD2, a member of the mSWI/SNF chromatin remodeling complex. The HOXB13/SMARCD2 interaction is stabilized through interactions with transcription factors. This interaction alters the chromatin accessibility at HOXB13 binding sites which leads to increased proliferation in PCa.

ORGANISM(S): Homo sapiens

PROVIDER: GSE228742 | GEO | 2025/11/18

REPOSITORIES: GEO

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HOXB13 alters chromatin accessibility in prostate cancer through interactions with the SWI/SNF complex [ChIP-seq ]

Project description:Homeobox-B13 (HOXB13) is a master transcriptional regulator which is exclusively expressed in the prostate tissue and has been shown to be crucial for its embryonic development. There is extensive clinical and experimental evidence to support the role of HOXB13 in prostate cancer (PCa). Yet, despite this critical role, the function of HOXB13 remains controversial with some studies supporting an oncogenic role and others demonstrating a tumor-suppressive role. While there is a clear relationship between HOXB13 and AR there are conflicting studies if HOXB13 is itself regulated by AR. Interrogating various AR +ve and AR -ve in-vivo and in-vitro models, in this study, we demonstrate that HOXB13 is crucial for the growth and proliferation of PCa regardless of its androgen dependency. We show that HOXB13 activity in these different models is mediated via interactions with cell-specific transcription factors. Yet despite the diverse transcription factor interactions, HOXB13 activity is commonly modulated by SMARCD2, a member of the mSWI/SNF chromatin remodeling complex. The HOXB13/SMARCD2 interaction is stabilized through interactions with transcription factors. This interaction alters the chromatin accessibility at HOXB13 binding sites which leads to increased proliferation in PCa.

2025-11-18 | GSE228743 | GEO

Targeting p300/CBP abolishes HOXB13 loss-induced lipogenesis and tumor metastasis [RNA-seq]

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

Targeting p300/CBP abolishes HOXB13 loss-induced lipogenesis and tumor metastasis [ChIP-seq]

2025-10-08 | GSE296236 | GEO

HOXB13 WT and G84E mass spectrometry

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.

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HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming [RNA-Seq]

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

HOXB13 inhibits lipid metabolism through HDAC3-mediated epigenetic reprogramming [ChIP-Seq]

2022-04-01 | GSE153583 | GEO

Hierarchical phosphorylation of HOXB13 by mTOR dictates its activity and oncogenic function in prostate cancer [RNAseq_HOXB13]

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

Diverse AR-V7 cistromes in castration-resistant prostate cancer are governed by HoxB13

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.

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Targeted Escalation of an Acetylated HOXB13-dependent Tyrosine Kinase Super-Enhancer Network Promotes Prostate Tumor Autonomy

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.

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Identification of HOXB13 binding sites in metastatic PC treated with Enzalutamide

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

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