Foxa1, also known as Forkhead box protein A1, is a pioneer transcription factor essential for the normal development of several endoderm-derived organs, including the prostate gland [2,3]. It induces open chromatin conformation, enabling the binding of other transcription factors. Through direct interactions with the Androgen Receptor (AR), it helps shape AR signaling, which drives the growth and survival of normal prostate and prostate cancer cells. It also has an AR-independent role in regulating epithelial-to-mesenchymal transition (EMT) [2].

In prostate cancer, FOXA1 mutations can be classified into different structural classes. Class-1 activating mutations in early prostate cancer enhance chromatin mobility and binding frequency, transactivating a luminal androgen-receptor program. Class-2 mutations in metastatic prostate cancers increase DNA affinity, promoting WNT-driven metastasis. Class-3 genomic rearrangements in metastatic cancers reposition a regulatory element to drive overexpression of FOXA1 or other oncogenes [3]. FOXA1 also regulates alternative splicing in prostate cancer. It binds to regulatory regions of splicing-related genes like HNRNPK and SRSF1, controlling trans-acting factor expression and influencing nonsense-mediated decay-targeted isoforms [1].

In conclusion, Foxa1 is crucial for organ development and plays a significant role in prostate cancer. Mutations and its regulatory functions in processes like alternative splicing and AR-related signaling highlight its importance in understanding prostate cancer development. The study of Foxa1 in prostate cancer through various models helps in elucidating the pathobiology of the disease and potentially developing new therapeutic strategies.

References:

1. Del Giudice, Marco, Foster, John G, Peirone, Serena, Rajan, Prabhakar, Cereda, Matteo. . FOXA1 regulates alternative splicing in prostate cancer. In Cell reports, 40, 111404. doi:10.1016/j.celrep.2022.111404. https://pubmed.ncbi.nlm.nih.gov/36170835/

2. Teng, Mona, Zhou, Stanley, Cai, Changmeng, Lupien, Mathieu, He, Housheng Hansen. 2020. Pioneer of prostate cancer: past, present and the future of FOXA1. In Protein & cell, 12, 29-38. doi:10.1007/s13238-020-00786-8. https://pubmed.ncbi.nlm.nih.gov/32946061/

3. Parolia, Abhijit, Cieslik, Marcin, Chu, Shih-Chun, Robinson, Dan R, Chinnaiyan, Arul M. 2019. Distinct structural classes of activating FOXA1 alterations in advanced prostate cancer. In Nature, 571, 413-418. doi:10.1038/s41586-019-1347-4. https://pubmed.ncbi.nlm.nih.gov/31243372/