PAX8 and MECOM are interaction partners driving ovarian cancer

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 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.

Integration of single-cell transcriptomes and chromatin landscapes reveals regulatory programs driving pharyngeal organ development

“…Finally, this approach reveals several TF-encoding genes without previously described roles in each respective tissue: Nfia (thymus), Scx (parathyroid), Prdm1 (UBB), and Mecom (thyroid). Given that a recent publication demonstrates that Mecom gene products interact with Pax8 to drive gene expression programs regulating cell adhesion and extracellular matrix formation 52 , our results could suggest a comparable interaction between Mecom and Pax8 to coordinate similar gene expression programs in the developing thyroid. Betweenness centrality of certain top regulators across all clusters revealed a distinctly cell-type-specific pattern, demonstrating the reliability of the CellOracle networks (Fig.…”

UCP1 modulates immune infiltration level and survival outcome in ovarian cancer patients

“…Several genes have been confirmed to be closely related to the occurrence and progression of ovarian cancer, including SNAI2 [ 16 ], VCAM1 [ 17 ], BRCA1 [ 18 ], MMP2 [ 19 ], MECOM [ 20 ], MXS1 [ 21 ], PARP1 [ 22 ] and so on. We further analyzed the association between UCP1 and these gene expression.…”

Comprehensive Analysis of E3 Ubiquitin Ligases Reveals Ring Finger Protein 223 as a Novel Oncogene Activated by KLF4 in Pancreatic Cancer

“…Among the eight prognostic markers, most have been reported in cancer. For instance, MDS1 and EVI1 complex loci (MECOM) interact with PAX8 and drive oncogenic functions in ovarian cancer ( Bleu et al, 2021 ). Cbl Proto-Oncogene C (CBLC) was demonstrated to enhance epidermal growth factor receptor dysregulation and signaling in lung adenocarcinoma ( Hong et al, 2018 ).…”