title: FOXA1 acts upstream of GATA2 and AR in hormonal regulation of gene expression.
abstract: Hormonal regulation of gene expression by androgen receptor (AR) is tightly controlled by many transcriptional cofactors, including pioneer factors FOXA1 and GATA2, which, however, exhibit distinct expression patterns and functional roles in prostate cancer. Here, we examined how FOXA1, GATA2 and AR crosstalk and regulate hormone-dependent gene expression in prostate cancer cells. Chromatin immunoprecipitation sequencing analysis revealed that FOXA1 reprograms both AR and GATA2 cistrome by preferably recruiting them to FKHD-containing genomic sites. By contrast, GATA2 is unable to shift AR or FOXA1 to GATA motifs. Rather, GATA2 co-occupancy enhances AR and FOXA1 binding to nearby ARE and FKHD sites, respectively. Similarly, AR increases, but not reprograms, GATA2 and FOXA1 cistromes. Concordantly, GATA2 and AR strongly enhance the transcriptional program of each other, whereas FOXA1 regulates GATA2- and AR-mediated gene expression in a context-dependent manner due to its reprogramming effects. Taken together, our data delineated for the first time the distinct mechanisms by which GATA2 and FOXA1 regulate AR cistrome and suggest that FOXA1 acts upstream of GATA2 and AR in determining hormone-dependent gene expression in prostate cancer.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Zhao
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: K-W
authors.initials: KW
authors.lastname: Fong
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: H-J
authors.initials: HJ
authors.lastname: Jin
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Y A
authors.initials: YA
authors.lastname: Yang
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Yu
mesh_terms: D045744:Cell Line, Tumor; D050989:GATA2 Transcription Factor / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000502:physiology*; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000235:genetics*; D011944:Receptors, Androgen / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: C410798:AR protein, human; C496499:FOXA1 protein, human; D050989:GATA2 Transcription Factor; C494711:GATA2 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; D011944:Receptors, Androgen