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, Giorgio G. Galli

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

41 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Artikelnummer3739
TijdschriftNature Communications
Volume10
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - 1 dec. 2019

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