Abstract 1847: The ubiquitin proteasome system controls cell cycle gene expression through regulation of histone acetylation in multiple myeloma

Transcription factors (TFs) are generally short-lived proteins that undergo active turnover. The dynamic interaction of TFs and co-regulators with promoters and enhancers allows cells to continuously adjust gene expression. Whereas the composition and binding of TFs at genomic sites is the focus of a widespread research effort, relatively little is known about how these complexes are removed by the ubiquitin-proteasome system (UPS). Multiple myeloma (MM), the second most common hematopoietic malignancy, has become a model disease for drugs that interfere with the UPS through either blocking or facilitating protein elimination. The proteasome inhibitor Bortezomib, for instance, is used as first-line treatment in MM. Since TFs are prime targets of proteasomal degradation, our research is focused on defining how nuclear proteolysis regulates transcriptional dynamics in this disease. This is of particular relevance since the therapeutic mechanisms of action of proteasome inhibitors are still ill-defined. Following proteasome inhibition in multiple myeloma cell lines, we performed chromatin-immunoprecipitation for histone H3 acetylation (K27) and multiple histone deacetylases (HDACs) and used next generation sequencing (ChIP-seq) to identify unique gene clusters that are actively regulated by the proteasome and quantify epigenetic changes in dependence of protein turnover. Our findings reveal that cell cycle and mitosis-related genes, particularly subsets of genes involved in centromere formation and sister chromatid segregation, are associated with nuclear protein turnover and transcriptionally repressed by proteasome inhibition. Among the main transcriptional co-repressor complexes, we found NCoR1 to play a key role in controlling MM growth by adjusting cell cycle gene expression. Following proteasome inhibition, stabilization of NCoR1 at the promoters of these genes favors the recruitment of histone deacetylases to further inhibit gene activity. Concordantly, analysis of a panel of MM patients shows that the expression levels of certain histone deacetylases correlate with patient survival, specifically when treated with proteasome inhibitors. We are currently examining how NCoR1 is degraded, with a particular emphasis on the impact on histone acetylation at cell cycle gene promoters. Exploring how histone modifications and proteasome activity crosstalk in a therapeutically relevant manner in MM will help us to better understand how this degradation pathway impacts myeloma proliferation. This research project will contribute to our understanding of epigenetic and transcriptional dynamics in MM. With our focus on the continuously changing abundance of TFs and co-regulators at promoters of cell cycle genes, we seek to unlock new therapeutical pathways and more specific targets for MM treatment compared to blunt proteasome inhibition. Citation Format: Laure Maneix, Polina Iakova, Shannon Moree, Luke Fletcher, Premal Lulla, Sarvari V. Yellapragada, Andre Catic. The ubiquitin proteasome system controls cell cycle gene expression through regulation of histone acetylation in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1847.