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Targeting p300 and CBP abolishes HOXB13-loss-induced lipogenesis and tumor metastasis
Xiaodong Lu1, Liu Peng1, Qi Chu1
1Department of Urology, Emory University School of Medicine, Atlanta, Georgia, USA.
Abstract:
HOXB13 is a prostate-specific transcription factor best known for its role as an androgen receptor (AR) cofactor. Recent evidence suggests that HOXB13 plays critical AR-independent functions in repressing lipogenic programs and promoting prostate cancer (PCa) metastasis. However, the mechanisms linking HOXB13 loss to tumor metastasis remain unclear. Here, we show that p300 and CBP co-occupy lipogenic enhancers suppressed by HOXB13 and HDAC3 and are essential for enhancer activation and target gene expression following HOXB13 depletion. Loss of HOXB13 induces lipid-sensitive matrix metalloproteinases (MMPs), promoting increased cell motility. Importantly, pharmacological inhibition of p300 and CBP blocks HOXB13-loss-driven lipogenesis, reduces MMP expression, and decreases cell migration in vitro and tumor metastasis in vivo. Analysis of clinical samples revealed that HOXB13 expression is reduced in metastatic hormone-sensitive PCa compared with matched primary tumors, further supporting its role in tumor metastasis. These findings demonstrate that HOXB13 downregulation promotes PCa metastasis through p300- and CBP-dependent lipogenic and motility pathways, which may be targeted by p300 inhibition.
Insights
Loss of HOXB13 transcription factor promotes prostate cancer metastasis by activating lipogenic and motility pathways. Targeting p300 and CBP may inhibit this process, offering a potential therapeutic strategy for metastatic prostate cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- HOXB13 is a prostate-specific transcription factor known for its role as an androgen receptor (AR) cofactor.
- Emerging evidence indicates HOXB13 has AR-independent functions in suppressing lipogenesis and inhibiting prostate cancer (PCa) metastasis.
Purpose of the Study:
- To elucidate the mechanisms by which HOXB13 loss contributes to PCa metastasis.
- To investigate the role of p300 and CBP in HOXB13-mediated regulation of lipogenesis and cell motility.
Main Methods:
- Investigated the co-occupancy of p300 and CBP at lipogenic enhancers.
- Assessed the impact of HOXB13 depletion on gene expression, including matrix metalloproteinases (MMPs).
- Utilized pharmacological inhibitors of p300 and CBP to evaluate their effects on lipogenesis, MMP expression, cell migration, and tumor metastasis in vitro and in vivo.
Main Results:
- HOXB13 loss leads to the co-occupation of p300 and CBP at lipogenic enhancers, driving target gene expression.
- HOXB13 downregulation induces lipid-sensitive MMPs, enhancing cell motility and promoting metastasis.
- Inhibition of p300 and CBP effectively blocks HOXB13-loss-driven lipogenesis, reduces MMP expression, and suppresses cell migration and tumor metastasis.
Conclusions:
- HOXB13 downregulation promotes PCa metastasis via p300- and CBP-dependent lipogenic and motility pathways.
- Reduced HOXB13 expression correlates with metastatic hormone-sensitive PCa in clinical samples.
- Targeting p300 inhibition presents a potential therapeutic strategy for inhibiting PCa metastasis.
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