title: Definition of a FoxA1 Cistrome that is crucial for G1 to S-phase cell-cycle transit in castration-resistant prostate cancer.
abstract: The enhancer pioneer transcription factor FoxA1 is a global mediator of steroid receptor (SR) action in hormone-dependent cancers. In castration-resistant prostate cancer (CRPC), FoxA1 acts as an androgen receptor cofactor to drive G₂ to M-phase cell-cycle transit. Here, we describe a mechanistically distinct SR-independent role for FoxA1 in driving G₁ to S-phase cell-cycle transit in CRPC. By comparing FoxA1 binding sites in prostate cancer cell genomes, we defined a codependent set of FoxA1-MYBL2 and FoxA1-CREB1 binding sites within the regulatory regions of the Cyclin E2 and E2F1 genes that are critical for CRPC growth. Binding at these sites upregulate the Cyclin E2 and Cyclin A2 genes in CRPC but not in earlier stage androgen-dependent prostate cancer, establishing a stage-specific role for this pathway in CRPC growth. Mechanistic investigations indicated that FoxA1, MYBL2, or CREB1 induction of histone H3 acetylation facilitated nucleosome disruption as the basis for codependent transcriptional activation and G₁ to S-phase cell-cycle transit. Our findings establish FoxA1 as a pivotal driver of the cell-cycle in CRPC which promotes G₁ to S-phase transit as well as G₂ to M-phase transit through two distinct mechanisms.
authors: Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Chunpeng
authors: C
authors: Zhang
authors: Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors: Liguo
authors: L
authors: Wang
authors: Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Dayong
authors: D
authors: Wu
authors: Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Hongyan
authors: H
authors: Chen
authors: Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Zhong
authors: Z
authors: Chen
authors: Division of Medical Oncology, Department of Internal Medicine and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Jennifer M
authors: JM
authors: Thomas-Ahner
authors: Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Debra L
authors: DL
authors: Zynger
authors: INSERM UMR 1011-Bâtiment J&K, Université Lille-Nord de France, Faculté de Médecine de, Lille-Pôle Recherche, Boulevard du Professeur Leclerc, Lille cedex, France.
authors: Jérôme
authors: J
authors: Eeckhoute
authors: Department of Medicine and Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
authors: Jindan
authors: J
authors: Yu
authors: Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Jun
authors: J
authors: Luo
authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
authors: Myles
authors: M
authors: Brown
authors: Division of Medical Oncology, Department of Internal Medicine and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Steven K
authors: SK
authors: Clinton
authors: Medical Sciences Program, Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Bloomington, Indiana.
authors: Kenneth P
authors: KP
authors: Nephew
authors: Human Cancer Genetics Program, Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio.
authors: Tim H-M
authors: TH
authors: Huang
authors: Division of Biostatistics, Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
authors: Wei
authors: W
authors: Li
authors: Department of Molecular and Cellular Biochemistry and the Comprehensive Cancer Center, The Ohio State University College of Medicine, Columbus, Ohio.
authors: Qianben
authors: Q
authors: Wang
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000728:Androgens; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D056751:Cyclin A2 / Q000096:biosynthesis / Q000235:genetics; D018450:Disease Progression; D050687:E2F1 Transcription Factor / Q000096:biosynthesis / Q000235:genetics; D016193:G1 Phase / Q000502:physiology*; D016195:G2 Phase / Q000502:physiology; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008677:Metaphase / Q000502:physiology; D009363:Neoplasm Proteins / Q000502:physiology*; D009376:Neoplasms, Hormone-Dependent / Q000235:genetics / Q000473:pathology; D009707:Nucleosomes / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D012045:Regulatory Sequences, Nucleic Acid; D016196:S Phase / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D000728:Androgens; C503721:CCNA2 protein, human; C115163:CREB1 protein, human; D018797:Cell Cycle Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D056751:Cyclin A2; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; C064352:MYBL2 protein, human; D009363:Neoplasm Proteins; D009707:Nucleosomes; D015534:Trans-Activators