# Targeting p300 and CBP abolishes HOXB13-loss-induced lipogenesis and tumor metastasis

## TL;DR

This study shows that losing HOXB13 in prostate cancer leads to metastasis through p300 and CBP, and blocking these proteins could be a new treatment strategy.

## Contribution

The paper identifies p300 and CBP as key drivers of HOXB13-loss-induced metastasis and lipogenesis in prostate cancer.

## Key findings

- HOXB13 loss activates p300 and CBP to drive lipogenic programs and MMP expression.
- Inhibiting p300 and CBP reduces lipogenesis, MMPs, and metastasis in prostate cancer models.
- HOXB13 expression is lower in metastatic tumors compared to primary tumors in clinical samples.

## 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.

HOXB13 loss promotes metastasis in prostate cancer via p300/CBP-driven lipogenesis and MMP induction, revealing a therapeutic vulnerability to p300/CBP inhibition.