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 cancers. 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. These include MDS1-EVI1 (also called PRDM3) 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 regulates 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, patient-derived xenografts (PDXs) 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 tumor growth, further supporting that the identified function of the MECOM locus underlies PAX8-driven oncogenic functions in ovarian cancer.
About The Expert
Melusine Bleu
Fanny Mermet-Meillon
Verena Apfel
Louise Barys
Laura Holzer
Marianne Bachmann Salvy
Rui Lopes
Inês Amorim Monteiro Barbosa
Cecile Delmas
Alexandra Hinniger
Suzanne Chau
Markus Kaufmann
Simon Haenni
Karolin Berneiser
Maria Wahle
Ivana Moravec
Alexandra Vissières
Tania Poetsch
Erik Ahrné
Nathalie Carte
Johannes Voshol
Elisabeth Bechter
Jacques Hamon
Marco Meyerhofer
Dirk Erdmann
Matteo Fischer
Therese Stachyra
Felix Freuler
Sascha Gutmann
César Fernández
Tobias Schmelzle
Ulrike Naumann
Guglielmo Roma
Kate Lawrenson
Cristina Nieto-Oberhuber
Amanda Cobos-Correa
Stephane Ferretti
Dirk Schübeler
Giorgio Giacomo Galli
References
PubMed