Bleu, Melusine, Grass, Verena, Mermet-Meillon, Fanny Anne-Marie, Barys, Louise, Holzer, Laura, Marques Lopes, Rui, Barbosa, Ines, Delmas, Cecile, Hinniger, Alexandra, Chau, Suzanne, Kaufmann, Markus, Haenni, Simon, Berneiser, Karolin Fiona, Wahle, Maria, Moravec, Ivana, Vissieres, Alexandra, Poetsch, Tania, Ahrne, Erik, Carte, Nathalie, Voshol, Johannes, Fischer, Matteo, Stachyra, Therese-Marie, Freuler, Felix, Gutmann, Sascha, Fernandez, Cesar, Naumann, Ulrike, Roma, Guglielmo, Schuebeler, Dirk, Nieto-Oberhuber, Cristina, Cobos-Correa, Amanda, Ferretti, Stephane Raymond and Galli, Giorgio (2021) PAX8 and MECOM are interaction partners driving Ovarian Carcinogenesis. Nature communications, 12. p. 2442. ISSN 2041-1723

Abstract

The transcription factor PAX8 is critical for the development of the thyroid and urogenital system. Comprehensive genomic screens furthermore indicate an additional oncogenic role for PAX8 in renal and ovarian carcinogenesis. While a plethora of PAX8-regulated genes in different contexts have been proposed, we still lack a mechanistic understanding of how PAX8 engages molecular complexes to drive disease-relevant oncogenic transcriptional programs. Here we show that protein isoforms originating from the MECOM locus form a complex with PAX8. This includes PRDM3 (also called MDS1-EVI1) for which we map its interaction with PAX8 in vitro and in vivo. We show that PAX8 binds a large number of genomic sites and forms transcriptional hubs. At a subset of these, PAX8 together with PRDM3 regulate a specific gene expression module involved in adhesion and extracellular matrix. This gene module correlates with PAX8 and MECOM expression in large scale profiling of cell lines, PTXs and clinical cases and stratifies gynecological cancer cases with worse prognosis. PRDM3 is amplified in Ovarian Cancers and we show that the MECOM locus and PAX8 sustain in-vivo ovarian cancer growth, further supporting that the identified function of the MECOM locus underlies PAX8-driven oncogenic functions in ovarian cancer.

Item Type:	Article
Date Deposited:	24 Jun 2021 00:45
Last Modified:	24 Jun 2021 00:45
URI:	https://oak.novartis.com/id/eprint/42966