Hierarchical phosphorylation of HOXB13 by mTOR dictates its activity and oncogenic function in prostate cancer [RNAseq_HOXB13]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA934501 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR23441715_1.fastq.gz | Fastqsanger.gz | |||
| SRR23441715_2.fastq.gz | Fastqsanger.gz | |||
| SRR23441716_1.fastq.gz | Fastqsanger.gz | |||
| SRR23441716_2.fastq.gz | Fastqsanger.gz | |||
| SRR23441717_1.fastq.gz | Fastqsanger.gz |
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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:Dysregulation of mTOR signaling plays a critical role in promoting prostate cancer growth. HOXB13, a homeodomain transcription factor, is known to influence the androgen response and prostate cancer 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 interaction with the E3 ligase SKP2 while enhancing its oncogenic properties. Expression of HOXB13 harboring phosphomimetic mutations at the mTOR-targeted sites stimulates prostate cancer 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 prostate cancer 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 prostate cancer.ImplicationsControl of HOXB13 transcriptional activity via its direct phosphorylation by the mTOR kinase is a potential therapeutic avenue for the management of advanced prostate cancer.
| S-EPMC10544006 | biostudies-literature
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 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: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 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:Tamoxifen resistant translational reprogramming is shown to be mediated by increased expression of eIF4E and its increased availability by hyperactive mTOR, and to require phosphorylation of eIF4E at Ser209 by increased MNK activity.
2017-12-21 | GSE107590 | 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 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