TY - JOUR
T1 - FOXA2 rewires AP-1 for transcriptional reprogramming and lineage plasticity in prostate cancer
AU - Wang, Zifeng
AU - Townley, Scott L.
AU - Zhang, Songqi
AU - Liu, Mingyu
AU - Li, Muqing
AU - Labaf, Maryam
AU - Patalano, Susan
AU - Venkataramani, Kavita
AU - Siegfried, Kellee R.
AU - Macoska, Jill A.
AU - Han, Dong
AU - Gao, Shuai
AU - Risbridger, Gail P.
AU - Taylor, Renea A.
AU - Lawrence, Mitchell G.
AU - He, Housheng Hansen
AU - Selth, Luke A.
AU - Cai, Changmeng
N1 - Funding Information:
This work is supported by grants from NIH (R01 CA211350 to C.C. and U54 CA156734 to C.C. and J.A.M.), DOD (W81XWH-19-1-0361 and W81XWH-21-1-0267 to C.C., and W81XWH-19-1-0777 to S.G.), CIHR (142246 and 159567 to H.H.H.), Cancer Council SA (2012127 to L.A.S.), Cancer Council NSW (2020404 to L.A.S.), Movember & National Breast Cancer Foundation Collaboration Initiative grant (MNBCF-17-012 to G.P.R. and L.A.S.), Department of Health and Human Services acting through the Victorian Cancer Agency (fellowships to M.G.L. MCRF18017, R.A.T. MCRF15023), the EJ Whitten Foundation, Movember (GAP Xenografting Consortium), the Peter and Lyndy White Foundation, TissuPath Pathology, and the Rotary Club of Manningham. L.A.S. is supported by a Principal Cancer Research Fellowship (PRF2919) awarded by Cancer Council\u2019s Beat Cancer project on behalf of its donors, the State Government through the Department of Health and the Australian Government through the Medical Research Future Fund. C.C. and D.H. were supported by Proposal Development Award from University of Massachusetts Boston. Z.W., M. Liu., and M. Li were supported by CSM (College of Science and Mathematics) Dean\u2019s Doctoral Research Fellowship from the University of Massachusetts Boston. M. Liu was supported by a graduate fellowship from the Integrative Biosciences Program at the University of Massachusetts Boston. We thank Camille OrtizCerezo, Yuhan Liu, Nolan Pattern, Krishna Patel, and Michaela Mulhearn for their assistance in various molecular assays and sequencing studies, Rachel Muriph and Dr. Evens for their assistance in the mass-spectrometry study, and other members of the Cai, Selth, Lawrence, and He laboratories for constructive input. We also thank Dr. Leigh Ellis for kindly providing SKO/DKO cell lines. We acknowledge the patient representatives, clinical coordinators, scientists, and clinicians, who contribute to the Melbourne Urological Research Alliance (MURAL) and its collection of patient-derived models.
Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85195430087&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-49234-9
DO - 10.1038/s41467-024-49234-9
M3 - Article
C2 - 38851846
AN - SCOPUS:85195430087
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4914
ER -
