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

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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
    College of Life Sciences, University of Chinese Academy of Sciences
    School of Life Science and Technology, ShanghaiTech University)

  • Hongyuan Chang

    (Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences
    College of Life Sciences, University of 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
    School of Life Sciences, Shanghai University)

  • Yingqun Yang

    (Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences
    College of Life Sciences, University of Chinese Academy of Sciences
    School of Life Science and Technology, ShanghaiTech University)

  • Peng Wang

    (Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences
    Shanghai Institute of Materia Medica, Chinese Academy of Sciences
    College of Life Sciences, University of Chinese Academy of Sciences
    School of Life Science and Technology, ShanghaiTech University)

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.

Suggested Citation

  • Mengzhu Xue & Haiyue Liu & Liwen Zhang & Hongyuan Chang & Yuwei Liu & Shaowei Du & Yingqun Yang & Peng Wang, 2017. "Computational identification of mutually exclusive transcriptional drivers dysregulating metastatic microRNAs in prostate cancer," Nature Communications, Nature, vol. 8(1), pages 1-9, April.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms14917
    DOI: 10.1038/ncomms14917
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