Targeting p300 and CBP abolishes HOXB13-loss-induced lipogenesis and tumor metastasis
Xiaodong Lu, Liu Peng, Qi Chu, Samantha Ye, Mingyang Liu, Maha Hussain, Mehmet A. Bilen, Lara R. Harik, Jonathan Melamed, Jonathan C. Zhao, Jindan Yu
Xiaodong Lu, Liu Peng, Qi Chu, Samantha Ye, Mingyang Liu, Maha Hussain, Mehmet A. Bilen, Lara R. Harik, Jonathan Melamed, Jonathan C. Zhao, Jindan Yu
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Research Article Genetics Oncology

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

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.

Authors

Xiaodong Lu, Liu Peng, Qi Chu, Samantha Ye, Mingyang Liu, Maha Hussain, Mehmet A. Bilen, Lara R. Harik, Jonathan Melamed, Jonathan C. Zhao, Jindan Yu

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Figure 6

Pharmacological inhibitors of p300 and CBP abolished HOXB13-low tumor metastasis.

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Pharmacological inhibitors of p300 and CBP abolished HOXB13-low tumor me...
(A) IVIS imaging of intravenous PC-3M xenograft tumors at weeks 0 (left) and 7 (right) after inoculation. Mice (n = 4 mice for pGIPZ vehicle group, n = 5 mice for the remaining groups) started treatment with CCS1477 on day 10. Heatmap shows IVIS signal intensity color scale. (B and C) Representative ex vivo IVIS images (B, n = 4 mice for pGIPZ vehicle group, n = 5 mice for the remaining groups) and quantifications (C) of PC-3M tumor metastasis to the lung and liver. Heatmap shows IVIS signal intensity color scale. Data are mean ± SD. Indicated P values were calculated by unpaired, 2-sided t test. (D) Graphical model illustrating HOXB13 as a molecular coordinator balancing HDAC3/NCoR and p300/CBP to fine-tune lipogenic gene expression in PCa. In HOXB13-high PCa cells, HOXB13 recruits the HDAC3-NCoR complex to lipogenic enhancers, catalyzing H3K27ac deacetylation and maintaining lipogenic gene expression at a basal level. In HOXB13-low PCa, this balance is disrupted — reduced recruitment of HDAC3 and NCoR leads to increased p300 and CBP binding and elevated H3K27ac levels at lipogenic enhancers. This results in aberrant activation of lipogenic programs, and induction of EMT-promoting genes such as MMPs.