Abstract Background: HOXB13 is a prostate-specific transcription factor best known for its role as an androgen receptor (AR) cofactor. We have previously reported that HOXB13 has an AR-independent function in repressing lipogenic programs via recruitment of HDAC3/NCoR in prostate cancer (PCa). This recruitment leads to deacetylation of H3K27 and suppression of lipid biosynthesis. Accordingly, HOXB13 loss is observed in approximately 30% of metastatic CRPC tumors. However, a direct link between HOXB13 loss and tumor metastasis remains unclear. Methods: ChIP-seq, RNA-seq, and functional assays (lipid staining, cell invasion) were performed in PCa cell lines (LNCaP, PC-3M, 22Rv1) with HOXB13 knockdown (KD), p300/CBP KD, or treatment with the p300/CBP inhibitor CCS1477. Immunohistochemistry (IHC) analyzed HOXB13 expression in 56 primary and 56 lymph node (LN) metastatic hormone-naive PCa samples (Emory cohort) and 80 hormone-treated PCa samples (NYU cohort). In vivo metastasis was evaluated using intravenous PC-3M xenografts treated with CCS1477. Results: Mechanistically, we found that p300/CBP co-occupy lipogenic enhancers with HOXB13/HDAC3. HOXB13 depletion increased H3K27ac and activated lipogenic genes, block p300/CBP suppressed these changes, indicating that p300/CBP are required for enhancer activation in the HOXB13-low state. Transcriptome analysis identified hundreds of HOXB13-loss-induced transcripts dependent on p300/CBP, especially enriched for steroid and fatty acid metabolism. Loss of HOXB13 also produced clear pro-metastatic phenotypes. Analysis of clinical samples showed reduced HOXB13 expression in lymph-node metastases from hormone-sensitive patients compared with matched primary tumors. Functionally, HOXB13 loss increased lipid accumulation and invasion, accompanied by upregulation of lipid-responsive MMPs, broad-spectrum MMP inhibition reduced invasion. Importantly, targeting p300/CBP effectively blocked the cascade of changes caused by HOXB13 downregulation. Similarly, HOXB13 knockdown increased metastasis in vivo, which was abolished by CCS1477 without apparent toxicity. Conclusion: Loss of HOXB13 disrupts the HOXB13/HDAC3-p300/CBP balance at lipogenic enhancers, increasing H3K27ac, lipogenesis, and lipid-responsive MMPs that drive PCa invasion and metastasis. Inhibition of p300/CBP reverses these phenotypes and thus may serve as a promising therapeutic strategy for metastatic hormone-sensitive PCa with low HOXB13. Citation Format: 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. Targeting p300/CBP abolishes HOXB13 loss-induced lipogenesis and tumor metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86 (8Suppl): Abstract nr LB301.
Lu et al. (Fri,) studied this question.