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.
Nature communications. 2024 Jun 08*** epublish ***
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
Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, 02125, USA., Flinders University, College of Medicine and Public Health, Flinders Health and Medical Research Institute, Bedford Park, SA, 5042, Australia., Department of Biology, University of Massachusetts Boston, Boston, MA, 02125, USA., Department of Cell Biology and Anatomy, New York Medical College, Valhalla, New York, 10595, USA., Melbourne Urological Research Alliance, Biomedicine Discovery Institute, Monash University, Melbourne, VIC, 3800, Australia., Department of Medical Biophysics, University of Toronto, Toronto, ON, M5G1L7, Canada., Center for Personalized Cancer Therapy, University of Massachusetts Boston, Boston, MA, 02125, USA. .