title: Integrative analysis identifies targetable CREB1/FoxA1 transcriptional co-regulation as a predictor of prostate cancer recurrence.
abstract: Identifying prostate cancer-driving transcription factors (TFs) in addition to the androgen receptor promises to improve our ability to effectively diagnose and treat this disease. We employed an integrative genomics analysis of master TFs CREB1 and FoxA1 in androgen-dependent prostate cancer (ADPC) and castration-resistant prostate cancer (CRPC) cell lines, primary prostate cancer tissues and circulating tumor cells (CTCs) to investigate their role in defining prostate cancer gene expression profiles. Combining genome-wide binding site and gene expression profiles we define CREB1 as a critical driver of pro-survival, cell cycle and metabolic transcription programs. We show that CREB1 and FoxA1 co-localize and mutually influence each other's binding to define disease-driving transcription profiles associated with advanced prostate cancer. Gene expression analysis in human prostate cancer samples found that CREB1/FoxA1 target gene panels predict prostate cancer recurrence. Finally, we showed that this signaling pathway is sensitive to compounds that inhibit the transcription co-regulatory factor MED1. These findings not only reveal a novel, global transcriptional co-regulatory function of CREB1 and FoxA1, but also suggest CREB1/FoxA1 signaling is a targetable driver of prostate cancer progression and serves as a biomarker of poor clinical outcomes.
authors.affiliation: Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Sunkel
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Dayong
authors.initials: D
authors.lastname: Wu
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Chiou-Miin
authors.initials: CM
authors.lastname: Wang
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Xiangtao
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Zhenqing
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Horning
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Devalingam
authors.initials: D
authors.lastname: Mahalingam
authors.affiliation: Department of Plant Pathology, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Horacio
authors.initials: H
authors.lastname: Lopez-Nicora
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Lin
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Goodfellow
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Clinton
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Victor X
authors.initials: VX
authors.lastname: Jin
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Chun-Liang
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors.forename: Tim H-M
authors.initials: TH
authors.lastname: Huang
authors.affiliation: Ohio State Biochemistry Program, The Ohio State University, Columbus, OH 43210, USA Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Columbus, OH 43210, USA The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA qianben.wang@osumc.edu.
authors.forename: Qianben
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001665:Binding Sites; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D016384:Consensus Sequence; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D018572:Disease-Free Survival; D015972:Gene Expression Regulation, Neoplastic; D063990:Gene Ontology; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000502:physiology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D056913:Mediator Complex Subunit 1 / Q000378:metabolism; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D014408:Biomarkers, Tumor; C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; C538855:MED1 protein, human; D056913:Mediator Complex Subunit 1; D047428:Protein Kinase Inhibitors