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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153583 | GEO | 2022/04/01

REPOSITORIES: GEO

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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

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

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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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Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

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Targeted Escalation of Tyrosine Kinase Super-Enhancer Network Engineered by Acetylated HOXB13 Spurs 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) 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.

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