Integrative analysis identifies targetable CREB1/FoxA1 transcriptional co-regulation as a predictor of prostate cancer recurrence. Nucleic Acids Res 2016 May 19;44(9):4105-22
Date
01/09/2016Pubmed ID
26743006Pubmed Central ID
PMC4872073DOI
10.1093/nar/gkv1528Scopus ID
2-s2.0-84969832986 (requires institutional sign-in at Scopus site) 30 CitationsAbstract
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.
Author List
Sunkel B, Wu D, Chen Z, Wang CM, Liu X, Ye Z, Horning AM, Liu J, Mahalingam D, Lopez-Nicora H, Lin CL, Goodfellow PJ, Clinton SK, Jin VX, Chen CL, Huang TH, Wang QAuthor
Victor X. Jin PhD Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgedAged, 80 and over
Base Sequence
Binding Sites
Biomarkers, Tumor
Cell Line, Tumor
Consensus Sequence
Cyclic AMP Response Element-Binding Protein
Disease-Free Survival
Gene Expression Regulation, Neoplastic
Gene Ontology
Hepatocyte Nuclear Factor 3-alpha
Humans
Kaplan-Meier Estimate
Male
Mediator Complex Subunit 1
Middle Aged
Neoplasm Recurrence, Local
Prognosis
Proportional Hazards Models
Prostatic Neoplasms
Protein Kinase Inhibitors
Signal Transduction
Transcription, Genetic
