1. PAX8 activates metabolic genes via enhancer elements in Renal Cell Carcinoma
- Author
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Judith Knehr, James E. Bradner, Charles Y. Lin, Valentina Cordoʹ, Audrey Kauffmann, Kathleen Sprouffske, Guglielmo Roma, Walter Carbone, Swann Gaulis, Giorgio G. Galli, Antonella F M Dost, Luca Tordella, Rui Lopes, Melusine Bleu, Umut Yildiz, Marco Pregnolato, Felix Lohmann, Verena Apfel, and Sjoerd J B Holwerda
- Subjects
0301 basic medicine ,Science ,General Physics and Astronomy ,Urological cancer ,02 engineering and technology ,Biology ,Article ,General Biochemistry, Genetics and Molecular Biology ,Histones ,03 medical and health sciences ,PAX8 Transcription Factor ,RNA interference ,Target identification ,Cell Line, Tumor ,Biomarkers, Tumor ,Gene silencing ,Humans ,RNA, Small Interfering ,Enhancer ,Promoter Regions, Genetic ,lcsh:Science ,Transcription factor ,Carcinoma, Renal Cell ,Epigenomics ,Cell Proliferation ,Regulation of gene expression ,Multidisciplinary ,Oncogene ,Ceruloplasmin ,Acetylation ,General Chemistry ,021001 nanoscience & nanotechnology ,Cancer metabolism ,Immunohistochemistry ,Kidney Neoplasms ,Cell biology ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Enhancer Elements, Genetic ,Cistrome ,Epigenetics ,RNA Interference ,lcsh:Q ,0210 nano-technology - Abstract
Transcription factor networks shape the gene expression programs responsible for normal cell identity and pathogenic state. Using Core Regulatory Circuitry analysis (CRC), we identify PAX8 as a candidate oncogene in Renal Cell Carcinoma (RCC) cells. Validation of large-scale functional genomic screens confirms that PAX8 silencing leads to decreased proliferation of RCC cell lines. Epigenomic analyses of PAX8-dependent cistrome demonstrate that PAX8 largely occupies active enhancer elements controlling genes involved in various metabolic pathways. We selected the ferroxidase Ceruloplasmin (CP) as an exemplary gene to dissect PAX8 molecular functions. PAX8 recruits histone acetylation activity at bound enhancers looping onto the CP promoter. Importantly, CP expression correlates with sensitivity to PAX8 silencing and identifies a subset of RCC cases with poor survival. Our data identifies PAX8 as a candidate oncogene in RCC and provides a potential biomarker to monitor its activity., Transcription factors are critical regulators of cell identity. Here, the authors use computational and functional genomic approaches to show an oncogenic role of PAX8 in renal cancer. Mechanistic dissection of PAX8 functions reveal its role in activating genes associated with metabolic pathways.
- Published
- 2019