Sunkel Benjamin, Wu Dayong, Chen Zhong, Wang Chiou-Miin, Liu Xiangtao, Ye Zhenqing, Horning Aaron M, Liu Joseph, Mahalingam Devalingam, Lopez-Nicora Horacio, Lin Chun-Lin, Goodfellow Paul J, Clinton Steven K, Jin Victor X, Chen Chun-Liang, Huang Tim H-M, Wang Qianben
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.
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.
Nucleic Acids Res. 2016 May 19;44(9):4105-22. doi: 10.1093/nar/gkv1528. Epub 2016 Jan 6.
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.
除雄激素受体外，识别前列腺癌驱动转录因子（TFs）有望提高我们有效诊断和治疗这种疾病的能力。我们对雄激素依赖性前列腺癌（ADPC）和去势抵抗性前列腺癌（CRPC）细胞系、原发性前列腺癌组织及循环肿瘤细胞（CTC）中的主要转录因子CREB1和FoxA1进行了综合基因组学分析，以研究它们在定义前列腺癌基因表达谱中的作用。结合全基因组结合位点和基因表达谱，我们将CREB1定义为促生存、细胞周期和代谢转录程序的关键驱动因子。我们发现CREB1和FoxA1共定位并相互影响彼此的结合，以定义与晚期前列腺癌相关的疾病驱动转录谱。在人类前列腺癌样本中的基因表达分析发现，CREB1/FoxA1靶基因面板可预测前列腺癌复发。最后，我们表明该信号通路对抑制转录共调节因子MED1的化合物敏感。这些发现不仅揭示了CREB1和FoxA1一种新的、全局转录共调节功能，还表明CREB1/FoxA1信号是前列腺癌进展的一个可靶向驱动因子，并作为不良临床结果的生物标志物。
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