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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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Xue M,Liu H,Zhang L,Chang H,Liu Y,Du S,Yang Y,Wang P

doi

10.1038/ncomms14917

subject

Has Abstract

pub_date

2017-04-11 00:00:00

pages

14917

issn

2041-1723

pii

ncomms14917

journal_volume

8

pub_type

杂志文章

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