Abstract
PAX8 is a prototype lineage-survival oncogene in epithelial ovarian cancer. However, neither its underlying pro-tumorigenic mechanisms nor potential therapeutic implications have been adequately elucidated. Here, we identified an ovarian lineage-specific PAX8 regulon using modified cancer outlier profile analysis, in which PAX8-FGF18 axis was responsible for promoting cell migration in an autocrine fashion. An image-based drug screen pinpointed that PAX8 expression was potently inhibited by small-molecules against histone deacetylases (HDACs). Mechanistically, HDAC blockade altered histone H3K27 acetylation occupancies and perturbed the super-enhancer topology associated with PAX8 gene locus, resulting in epigenetic downregulation of PAX8 transcripts and related targets. HDAC antagonists efficaciously suppressed ovarian tumor growth and spreading as single agents, and exerted synergistic effects in combination with standard chemotherapy. These findings provide mechanistic and therapeutic insights for PAX8-addicted ovarian cancer. More generally, our analytic and experimental approach represents an expandible paradigm for identifying and targeting lineage-survival oncogenes in diverse human malignancies.
Highlights
Mammalian development proceeds in a hierarchical manner involving directed differentiation from pluripotent stem cells to lineage-committed precursors, which subsequently propagate and progressively yield terminal progeny that constitute the bulk of functional organs
A high-throughput image-based small-molecule screen identified that various histone deacetylase (HDAC) inhibitors, including FDA-approved panobinostat (FARYDAK) and romidepsin (ISTODAX), epigenetically abrogated PAX8 expression and efficaciously suppressed xenografts progression, and represent promising repurposing opportunities to treat patients affected by epithelial ovarian cancer and potentially other human malignancies driven by lineage-survival oncogenes
On the basis of these data, we proposed that chemotherapy combined with HDAC inhibitors might represent a valuable therapeutic option to produce robust and durable benefit for ovarian cancer patients featured by PAX8 dependency
Summary
Mammalian development proceeds in a hierarchical manner involving directed differentiation from pluripotent stem cells to lineage-committed precursors, which subsequently propagate and progressively yield terminal progeny that constitute the bulk of functional organs. This process, spatiotemporally co-opting cell fate specification and proliferation, is exquisitely guided by tissue-specific regulators of the gene expression program, oftentimes a remarkably small number of master transcription factors (Mohn and Schubeler, 2009). A high-throughput image-based small-molecule screen identified that various histone deacetylase (HDAC) inhibitors, including FDA-approved panobinostat (FARYDAK) and romidepsin (ISTODAX), epigenetically abrogated PAX8 expression and efficaciously suppressed xenografts progression, and represent promising repurposing opportunities to treat patients affected by epithelial ovarian cancer and potentially other human malignancies driven by lineage-survival oncogenes
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