PAX8 activates metabolic genes via enhancer elements in Renal Cell Carcinoma

Melusine Bleu, Swann Gaulis, Rui Lopes, Kathleen Sprouffske, Verena Apfel, Sjoerd Holwerda, Marco Pregnolato, Umut Yildiz, Valentina Cordoʹ, Antonella F. M. Dost, Judith Knehr, Walter Carbone, Felix Lohmann, Charles Y. Lin, James E. Bradner, Audrey Kauffmann, Luca Tordella, Guglielmo Roma and Giorgio G. Galli ()
Additional contact information
Melusine Bleu: Disease Area Oncology, Novartis Institute for Biomedical Research
Swann Gaulis: Disease Area Oncology, Novartis Institute for Biomedical Research
Rui Lopes: Disease Area Oncology, Novartis Institute for Biomedical Research
Kathleen Sprouffske: Disease Area Oncology, Novartis Institute for Biomedical Research
Verena Apfel: Disease Area Oncology, Novartis Institute for Biomedical Research
Sjoerd Holwerda: Chemical Biology & Therapeutics, Novartis Institutes for Biomedical Research
Marco Pregnolato: Disease Area Oncology, Novartis Institute for Biomedical Research
Umut Yildiz: Disease Area Oncology, Novartis Institute for Biomedical Research
Valentina Cordoʹ: Disease Area Oncology, Novartis Institute for Biomedical Research
Antonella F. M. Dost: Disease Area Oncology, Novartis Institute for Biomedical Research
Judith Knehr: Chemical Biology & Therapeutics, Novartis Institutes for Biomedical Research
Walter Carbone: Chemical Biology & Therapeutics, Novartis Institutes for Biomedical Research
Felix Lohmann: Chemical Biology & Therapeutics, Novartis Institutes for Biomedical Research
Charles Y. Lin: Baylor College of Medicine
James E. Bradner: Novartis Institutes for Biomedical Research
Audrey Kauffmann: Disease Area Oncology, Novartis Institute for Biomedical Research
Luca Tordella: Disease Area Oncology, Novartis Institute for Biomedical Research
Guglielmo Roma: Chemical Biology & Therapeutics, Novartis Institutes for Biomedical Research
Giorgio G. Galli: Disease Area Oncology, Novartis Institute for Biomedical Research

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-11672-1

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