2. Academic Validation
  3. Targeting p300 and CBP abolishes HOXB13-loss-induced lipogenesis and tumor metastasis

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

  • JCI Insight. 2025 Nov 24;10(22):e195743. doi: 10.1172/jci.insight.195743.
Xiaodong Lu 1,  Liu Peng 1,  Qi Chu 1,  Samantha Ye 1,  Mingyang Liu 1,  Maha Hussain 2,  Mehmet A Bilen 3 4,  Lara R Harik 4 5,  Jonathan Melamed 6,  Jonathan C Zhao 4 7,  Jindan Yu 1 4 7
Affiliations

Affiliations

  • 1 Department of Urology, Emory University School of Medicine, Atlanta, Georgia, USA.
  • 2 Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.
  • 3 Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, USA.
  • 4 Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
  • 5 Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
  • 6 Department of Pathology at NYU Grossman School of Medicine, New York, New York, USA.
  • 7 Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, USA.
PMID: 41277556 DOI: 10.1172/jci.insight.195743
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.

Keywords

Drug therapy; Epigenetics; Genetics; Oncology; Prostate cancer.

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