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Computational identification of mutually exclusive transcriptional drivers dysregulating metastatic microRNAs in
Mengzhu Xue1, Haiyue Liu1, Liwen Zhang2,3,4
1Laboratory of Systems Biology, Shanghai Advanced Research Institute, Chinese Academy of Sciences, No. 100 Haike Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201210, China.
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.
Insights
Researchers identified three master transcription factors (TFs) that drive metastatic prostate cancer progression and resistance to androgen-ablation therapy. Their mutually exclusive overexpression enhances cell motility and predicts poor clinical outcomes, offering new therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Androgen-ablation therapies are standard for metastatic prostate cancer but invariably lead to resistance.
- Understanding the molecular mechanisms driving metastasis and resistance is crucial for developing effective treatments.
- MicroRNA dysregulation is implicated in metastatic prostate cancer, but the underlying drivers are poorly understood.
Purpose of the Study:
- To systematically identify key transcription factors (TFs) driving aberrant microRNA expression in metastatic prostate cancer.
- To investigate the role of identified TFs in promoting metastasis and clinical outcomes.
- To explore the potential of TF mutual exclusivity as a characteristic of tumorigenesis.
Main Methods:
- Integrative analysis of transcription factor (TF) and microRNA expression profiles.
- Computational identification of master TFs regulating microRNA expression.
- Experimental validation of TF-microRNA interactions and functional impact on cell motility.
- Correlation analysis with clinical outcomes and cross-tissue/cancer validation.
Main Results:
- Three master TFs (AR, HOXC6, NKX2-2) were identified that induce aberrant metastatic microRNA expression in a mutually exclusive manner.
- Experimental validation confirmed co-dysregulation of numerous metastasis-associated microRNAs by these TFs.
- Overexpression of these TFs significantly enhanced cell motility and was associated with poor clinical outcomes.
- Mutually exclusive overexpression of AR, HOXC6, and NKX2-2 was observed across various tissues and cancers.
Conclusions:
- AR, HOXC6, and NKX2-2 are key drivers of metastatic prostate cancer progression through microRNA dysregulation.
- The mutually exclusive overexpression of these TFs represents a potential vulnerability and characteristic of tumorigenesis.
- Targeting these master TFs or their downstream microRNAs could offer novel therapeutic strategies for prostate cancer.