Computational identification of mutually exclusive transcriptional drivers dysregulating metastatic microRNAs in prostate cancer

Mengzhu Xue, Haiyue Liu, Liwen Zhang, Hongyuan Chang, Yuwei Liu, Shaowei Du, Yingqun Yang and Peng Wang ()
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Mengzhu Xue: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences
Haiyue Liu: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences
Liwen Zhang: Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Hongyuan Chang: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences
Yuwei Liu: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences
Shaowei Du: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences
Yingqun Yang: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences
Peng Wang: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences

Nature Communications, 2017, vol. 8, issue 1, 1-9

Abstract: Abstract Androgen-ablation therapies, which are the standard treatment for metastatic prostate cancer, invariably lead to acquired resistance. Hence, a systematic identification of additional drivers may provide useful insights into the development of effective therapies. Numerous microRNAs that are critical for metastasis are dysregulated in metastatic prostate cancer, but the underlying molecular mechanism is poorly understood. We perform an integrative analysis of transcription factor (TF) and microRNA expression profiles and computationally identify three master TFs, AR, HOXC6 and NKX2-2, which induce the aberrant metastatic microRNA expression in a mutually exclusive fashion. Experimental validations confirm that the three TFs co-dysregulate a large number of metastasis-associated microRNAs. Moreover, their overexpression substantially enhances cell motility and is consistently associated with a poor clinical outcome. Finally, the mutually exclusive overexpression between AR, HOXC6 and NKX2-2 is preserved across various tissues and cancers, suggesting that mutual exclusivity may represent an intrinsic characteristic of driver TFs during tumorigenesis.

Date: 2017
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DOI: 10.1038/ncomms14917

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