1. Multi-omics analysis reveals contextual tumor suppressive and oncogenic gene modules within the acute hypoxic response
- Author
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Zdenek Andrysik, Heather Bender, Matthew D. Galbraith, and Joaquín M. Espinosa
- Subjects
Transcriptional Activation ,0301 basic medicine ,Transcription, Genetic ,Cellular adaptation ,Cell Survival ,Science ,General Physics and Astronomy ,Biology ,medicine.disease_cause ,Article ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,Cell Line, Tumor ,Neoplasms ,Transcription factors ,medicine ,Humans ,Gene Regulatory Networks ,Genes, Tumor Suppressor ,RNA, Messenger ,Kinase activity ,Hypoxia ,Transcriptomics ,PI3K/AKT/mTOR pathway ,Cancer ,Regulation of gene expression ,Multidisciplinary ,Genome, Human ,TOR Serine-Threonine Kinases ,Genomics ,Oncogenes ,General Chemistry ,Cyclin-Dependent Kinase 8 ,Hypoxia-Inducible Factor 1, alpha Subunit ,Up-Regulation ,Cell biology ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,HIF1A ,030220 oncology & carcinogenesis ,Disease Progression ,Cyclin-dependent kinase 8 ,Carcinogenesis ,Transcription ,Protein Binding ,Genetic screen - Abstract
Cellular adaptation to hypoxia is a hallmark of cancer, but the relative contribution of hypoxia-inducible factors (HIFs) versus other oxygen sensors to tumorigenesis is unclear. We employ a multi-omics pipeline including measurements of nascent RNA to characterize transcriptional changes upon acute hypoxia. We identify an immediate early transcriptional response that is strongly dependent on HIF1A and the kinase activity of its cofactor CDK8, includes indirect repression of MYC targets, and is highly conserved across cancer types. HIF1A drives this acute response via conserved high-occupancy enhancers. Genetic screen data indicates that, in normoxia, HIF1A displays strong cell-autonomous tumor suppressive effects through a gene module mediating mTOR inhibition. Conversely, in advanced malignancies, expression of a module of HIF1A targets involved in collagen remodeling is associated with poor prognosis across diverse cancer types. In this work, we provide a valuable resource for investigating context-dependent roles of HIF1A and its targets in cancer biology., The response to hypoxia can significantly impact oncogenic processes. Here, the authors define the early transcriptional response to acute hypoxia and identify HIF1A target genes as part of this acute response, providing a resource for investigating context-dependent roles of HIF1A in the biology of cancer.
- Published
- 2021