Transcription factors (TFs) regulate gene expression through "enhanceosomes," multi-protein complexes that assemble at enhancer elements to modulate chromatin accessibility and transcriptional activity. In cancer, these become "neo-enhanceosomes," driving oncogenic programs by engaging aberrant or amplified lineage-specific enhancers. Prostate cancer (PCa) exemplifies this, with androgen receptor (AR) and TFs like FOXA1 and ERG playing central roles. We identify FOXA1 mutations that alter chromatin, activate oncogenic pathways, and drive metastasis. Using engineered mouse models and isogenic cell lines, we reveal FOXA1 mutations' mechanistic contributions to PCa progression and resistance. We further explore therapeutic strategies targeting neo-enhanceosome function, leveraging small-molecule degraders of chromatin remodelers like mSWI/SNF complex. Preclinical models demonstrate mSWI/SNF ATPase degraders’ efficacy, alone or with AR antagonists, inhibit tumor growth and overcome treatment resistance in castration-resistant PCa. This work highlights neo-enhanceosomes' critical role in oncogenesis and the potential of targeting enhancer-driven transcription in PCa and other cancers.

HOST
Prof Patrick Tan
Senior Vice Dean, Research
Duke-NUS Medical School

DATE
Tuesday, 21 January 2025

TIME
12.00 PM - 1.00 PM
(Light refreshments will be served at 11.30 AM)

VENUE
Duke-NUS Medical School
Amphitheatre, Level 2

CONTACT PERSON
Ms Serene Wie (serene.wie@duke-nus.edu.sg)
Duke-NUS Research Affairs Department