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 and Changmeng Cai ()
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Zifeng Wang: University of Massachusetts Boston
Scott L. Townley: Flinders Health and Medical Research Institute
Songqi Zhang: University of Massachusetts Boston
Mingyu Liu: University of Massachusetts Boston
Muqing Li: University of Massachusetts Boston
Maryam Labaf: University of Massachusetts Boston
Susan Patalano: University of Massachusetts Boston
Kavita Venkataramani: University of Massachusetts Boston
Kellee R. Siegfried: University of Massachusetts Boston
Jill A. Macoska: University of Massachusetts Boston
Dong Han: University of Massachusetts Boston
Shuai Gao: New York Medical College, Valhalla
Gail P. Risbridger: Monash University
Renea A. Taylor: Monash University
Mitchell G. Lawrence: Monash University
Housheng Hansen He: University of Toronto
Luke A. Selth: Flinders Health and Medical Research Institute
Changmeng Cai: University of Massachusetts Boston

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-49234-9

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