title: Computational identification of mutually exclusive transcriptional drivers dysregulating metastatic microRNAs in prostate cancer.
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.
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, No. 100 Haike Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201210, China.
authors.forename: Mengzhu
authors.initials: M
authors.lastname: Xue
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, No. 100 Haike Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201210, China.
authors.forename: Haiyue
authors.initials: H
authors.lastname: Liu
authors.affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203, China.|College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Shijingshan District, Beijing 100049, China.|School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai 201210, China.
authors.forename: Liwen
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, No. 100 Haike Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201210, China.|College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Shijingshan District, Beijing 100049, China.
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Chang
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, No. 100 Haike Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201210, China.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, No. 100 Haike Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201210, China.|School of Life Sciences, Shanghai University, 99 Shangda Road, BaoShan District, Shanghai 200444, China.
authors.forename: Shaowei
authors.initials: S
authors.lastname: Du
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, No. 100 Haike Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201210, China.|College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Shijingshan District, Beijing 100049, China.|School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai 201210, China.
authors.forename: Yingqun
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, No. 100 Haike Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201210, China.|Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Zhang Jiang Hi-Tech Park, Pudong, Shanghai 201203, China.|College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Shijingshan District, Beijing 100049, China.|School of Life Science and Technology, ShanghaiTech University, 393 Middle Huaxia Road, Pudong, Shanghai 201210, China.
authors.forename: Peng
authors.identifier: 0000-0002-2972-7495
authors.initials: P
authors.lastname: Wang
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D029961:Zebrafish Proteins
chemical_list: C094289:HOXC6 protein, human; D000090322:Homeobox Protein Nkx-2.2; D018398:Homeodomain Proteins; D035683:MicroRNAs; C000715631:NKX2-2 protein, human; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000715630:nkx2.2b protein, zebrafish