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.
Highlights
Androgen-ablation therapies, which are the standard treatment for metastatic prostate cancer, invariably lead to acquired resistance
Our mutually exclusive driver transcription factor (TF) hypothesis suggests that while the aberrant expression of metastasis-associated miRNAs is consistently observed across all metastatic cancer samples, each of the driver TFs dysregulating metastasis-associated miRNAs is only overexpressed in a subset of metastatic cancer samples, and in a mutually exclusive fashion
Instead of a single miRNA, a driver TF should dysregulate the vast majority of miRNAs differentially expressed in metastatic prostate cancer; second, cancer samples overexpressing the driver TFs should form a mutually exclusive pattern such that each driver TF dysregulates metastatic miRNA expression in a distinct subset of cancer samples, and these sets of samples demonstrate statistically significant tendencies towards mutual exclusivity; and third, those driver TFs should command statistically significant overlap in their miRNA targets, dysregulate the same metastasis-associated miRNA programme
Summary
Androgen-ablation therapies, which are the standard treatment for metastatic prostate cancer, invariably lead to acquired resistance. 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. Glucocorticoid receptor (GR) has been identified to reactivate the AR transcriptome in the absence of AR in patients resistant to enzalutamide[1], an anti-androgen drug, suggesting that mutual exclusivity, which broadly characterizes cancer-driving aberrations in signalling pathways[5], dictates driver TFs that reactivate the AR transcriptome in CRPC. We perform a computational prediction and identify a module of mutually exclusive transcriptional drivers, AR, HOXC6 and NKX2-2, which co-dysregulate a core set of metastasisassociated miRNAs in prostate cancer. Our findings indicate that mutual exclusivity, which represents an intrinsic property of oncogenic aberrations in signalling pathways, may broadly characterize transcriptional drivers of gene regulatory networks during tumorigenesis
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