PAX8 and MECOM are interaction partners driving ovarian cancer
Melusine Bleu1, Fanny Mermet-Meillon1, Verena Apfel1
1Disease area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland.
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.
Insights
The transcription factor PAX8 interacts with MECOM proteins, including PRDM3, to regulate genes involved in cell adhesion. This interaction drives oncogenic transcriptional programs in ovarian and kidney cancers, impacting patient prognosis.
Area of Science:
- Molecular biology
- Cancer research
- Genomics
Background:
- The transcription factor PAX8 is essential for thyroid and urogenital development.
- PAX8 also plays an oncogenic role in renal and ovarian cancers.
- Mechanistic understanding of PAX8's oncogenic transcriptional programs is lacking.
Purpose of the Study:
- Investigate the molecular complexes PAX8 engages in to drive oncogenic transcriptional programs.
- Elucidate the role of MECOM locus proteins in PAX8-driven cancers.
Main Methods:
- In vitro and in vivo mapping of PAX8-PRDM3 interaction.
- Genomic site analysis of PAX8 binding.
- Gene expression profiling in cell lines, PDXs, and clinical cases.
- Analysis of MECOM locus amplification and its effect on tumor growth.
Main Results:
- PAX8 forms a complex with MECOM protein isoforms, including PRDM3.
- PAX8 and PRDM3 co-regulate a gene expression module involved in adhesion and extracellular matrix.
- This gene module correlates with PAX8 and MECOM expression and predicts worse prognosis in gynecological cancers.
- MECOM locus amplification and PAX8 drive tumor growth in vivo.
Conclusions:
- The MECOM locus, through its interaction with PAX8 and PRDM3, contributes to oncogenic transcriptional programs in ovarian and renal cancers.
- The identified PAX8-MECOM interaction is a key driver of PAX8-associated oncogenesis, particularly in ovarian cancer.
- This finding provides a mechanistic link between PAX8, MECOM, and cancer progression, with potential implications for patient stratification.
More Related Videos
09:08Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
Published on: January 12, 2020
09:40Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Related Concept Videos
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:23Abnormal Proliferation
01:12Loss of Tumor Suppressor Gene Functions
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...