title: Disrupted cooperation between transcription factors across diverse cancer types.
abstract: Transcription Factors (TFs), essential for many cellular processes, generally work coordinately to induce transcriptional change in response to internal and external signals. Disrupted cooperation between TFs, leading to dysregulation of target genes, contributes to the pathogenesis of many diseases, including cancer. Although the aberrant activation of individual TFs and the functional effects have been widely studied, the perturbation of TF cooperativity in cancer has rarely been explored.
  
  
  
  We used TF co-expression as proxy as cooperativity and performed a large-scale study on disrupted TF cooperation across seven cancer types. While the connectivity of downstream effectors, like metabolic genes and TF targets, were more or similarly disrupted than/with non-TFs, the cooperativity of TFs (upstream regulators) were consistently less disturbed in all studied cancer types. Highly coordinated TFs in normal, however, generally lost that cooperation in cancer. Although different types of cancer shared very few TF pairs with highly disrupted cooperation, the cooperativity of interferon regulatory factors (IRF) was highly disrupted in six cancer types. Specifically, the cooperativity of IRF8 was highly perturbed in lung cancer, which was further validated by two independent lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) datasets. More interestingly, the cooperativity of IRF8 was markedly associated with tumor progression and even contributed to the patient survival independent of tumor stage.
  
  
  
  Our findings underscore the far more important role of TF cooperativity in tumorigenesis than previously appreciated. Disrupted cooperation of TFs provides potential clinical utility as prognostic markers for predicting the patient survival.
authors: Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Jing
authors: 0000-0003-2775-9001
authors: J
authors: Wang
authors: Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA.|Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors: Qi
authors: Q
authors: Liu
authors: School of Biomedical Informatics, The University of Texas Health Science Center at Houston, Houston, TX, USA.
authors: Jingchun
authors: J
authors: Sun
authors: Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN, USA. yu.shyr@vanderbilt.edu.|Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA. yu.shyr@vanderbilt.edu.|Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA. yu.shyr@vanderbilt.edu.
authors: Yu
authors: Y
authors: Shyr
mesh_terms: D002352:Carrier Proteins; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011485:Protein Binding; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D014157:Transcription Factors
keywords: Co-expression; Cooperation disruption; Pan-cancer; TF cooperation; Transcription factors