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 3

HOXB13 is downregulated in metastatic hormone-sensitive prostate cancer.

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HOXB13 is downregulated in metastatic hormone-sensitive prostate cancer....
(A) Representative images of HOXB13 staining in primary tumors (top) and lymph node–metastatic PCa (LN Mets, bottom) are shown in low (×4) and high (×40) magnification. “T” indicates tumor in LN Mets. (B) Quantification of HOXB13 IHC staining intensities in primary PCa and LN Mets. P value was calculated by unpaired, 2-sided t test. Box-and-whisker plots represent the median (line) and bottom and upper quartiles (box bounds); whisker edges indicate the minimum and maximum values. (C) Quantification of HOXB13 IHC staining intensities in paired primary PCa and LN Mets. Data are shown as in B. P value was calculated by paired, 2-sided t test. (D) Representative images of HOXB13 staining in primary PCa from hormone treatment–naive patients (hormone naive, HN; left), or from patients with hormone therapy less than 2 months (hormone received, HR<2M, middle), or from patients with hormone therapy more than 2 months (hormone received, HR>2M, right). The images are shown in low (×10, top) and high (×40, bottom) magnification. (E) Quantification of HOXB13 IHC staining intensities in PCa samples from D. Data are shown as in B. P value was calculated by 1-way ANOVA followed by Tukey’s multiple-comparison test.