FOXA2 rewires AP-1 for transcriptional reprogramming and lineage plasticity in prostate cancer

Zifeng Wang, Scott L. Townley, Songqi Zhang, Mingyu Liu, Muqing Li, Maryam Labaf, Susan Patalano, Kavita Venkataramani, Kellee R. Siegfried, Jill A. Macoska, Dong Han, Shuai Gao, Gail P. Risbridger, Renea A. Taylor, Mitchell G. Lawrence, Housheng Hansen He, Luke A. Selth, Changmeng Cai

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Abstract

FOXA family proteins act as pioneer factors by remodeling compact chromatin structures. FOXA1 is crucial for the chromatin binding of the androgen receptor (AR) in both normal prostate epithelial cells and the luminal subtype of prostate cancer (PCa). Recent studies have highlighted the emergence of FOXA2 as an adaptive response to AR signaling inhibition treatments. However, the role of the FOXA1 to FOXA2 transition in regulating cancer lineage plasticity remains unclear. Our study demonstrates that FOXA2 binds to distinct classes of developmental enhancers in multiple AR-independent PCa subtypes, with its binding depending on LSD1. Moreover, we reveal that FOXA2 collaborates with JUN at chromatin and promotes transcriptional reprogramming of AP-1 in lineage-plastic cancer cells, thereby facilitating cell state transitions to multiple lineages. Overall, our findings underscore the pivotal role of FOXA2 as a pan-plasticity driver that rewires AP-1 to induce the differential transcriptional reprogramming necessary for cancer cell lineage plasticity.

Original languageEnglish
Article number4914
Number of pages20
JournalNature Communications
Volume15
Issue number1
DOIs
Publication statusPublished - 8 Jun 2024

Keywords

  • Cancer epigenetics
  • Prostate cancer

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