EPICAL · Systematic Identification and Validation of Epigenetic Cancer Lesions by Chemical Biology and Functional Genomics
FP7 — People (Marie Curie Actions)
- Duration
- 2011-12-01 → 2015-11-30
- EU contribution
- €100,000
- Participants
- 1
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
Systematic Identification and Validation of Epigenetic Cancer Lesions by Chemical Biology and Functional Genomics
Many epigenetic factors contribute to cancer development and progression by altering chromatin structure and gene expression, thereby controlling pro-proliferative and anti-apoptotic properties. While some of these proteins are well-studied, the role of the majority of the ~400 chromatin-modifying proteins remains elusive. These chromatin modifiers fall into the categories of epigenetic ‘writers’ (DNA methyltranserases, histone methyltransferases, acetyltransferases, kinases, ubiquitinases) and ‘erasers’ (histone demethylases, deacetylases, phosphatases, deubiquitinases), chromatin modification binders (‘readers’; e.g. bromo, PHD, chromo, tudor domains) and chromatin remodelers. Epigenetic factors have been recognized as potential drug targets in the pharmaceutical industry, and small molecules inhibiting several chromatin modifying enzymes have been developed: four HDAC inhibitors are now approved for the treatment of cutaneous T-cell lymphoma and two DNA methyltransferase inhibitors are used in myelodysplastic syndrome. In addition, more than 30 other chromatin-targeting compounds are currently under clinical investigation. While DNA methyltransferases and histone deacetylases are well-established drug-targets, the enzymes regulating histone lysine methylation are less studied and only now are first methyltransferase inhibitor entering the clinic. In the human genome, around 50 histone methyltransferases and 30 histone demethylases are encoded, and they specifically target certain lysines (histone H3K4, H3K9, H3K27, H3K36, H3K79, H4K20) and methylation states (mono, di-, or tri-methylation). Currently, only tool compounds are available to regulate the activity of histone methyltransferases and specific compounds are not yet available for histone methyl binding proteins. Furthermore, the functional link between genetic alterations of the genes encoding these enzymes and increased proliferation in a cancerous state is less well established. Within EPICAL, we systematically studied chromatin proteins in cancer using epigenome-wide knock-down studies and small molecule probes. To this aim, we assembled libraries of small molecules and shRNA constructs targeting different chromatin modifiers. In an epigenome-wide screen we discovered the sensitivity of NOTCH-activated breast cancer cells to the inhibition of SUMOylation, suggesting the development of high-affinity chemical probes targeting this posttranslational modification for in vivo validation.
Data: CORDIS, © European Union
Project objective
Epigenetic pathways contribute to cancer development and progression. These pathways act via proteins that modulate chromatin structure and gene expression, and can thereby give pro-proliferative and anti-apoptotic properties selected for in cancer. In total ~400 factors are known that either modify chromatin directly as epigenetic ‘writers’ (DNA methyltranserases, histone methyltransferases, acetyltransferases, kinases, ubiquitinases) and ‘erasers’ (histone demethylases, deacetylases, phosphatases, deubiquitinases) or indirectly by moving nucleosomes (‘remodelers’) or binding to the modifications set by the ‘writers’ (‘readers’; e.g. bromo, PHD, chromo, tudor domains). Small molecules inhibiting several chromatin modifying enzymes have been developed, and HDAC inhibitors and DNA methyltransferase inhibitors are approved drugs. While DNA methyltransferases and histone deacetylases are well-established drug-targets, the majority of the ~400 chromatin modifiers is not studied in cancer. Furthermore, the functional link between genetic alterations of the genes encoding these enzymes and increased proliferation in a cancerous state is less well established.Here we propose to generate and apply tools to systematically study these proteins in cancer using epigenome-wide knock-down studies and small molecule probes. This project directly benefits from the experience at the Broad Institute, where Stefan Kubicek worked for 3.5 years, which allowed him to bring to CeMM a library of knock-down constructs targeting all chromatin proteins in collaboration with the Broad RNAi platform. Similarly, his work on histone demethylases has yielded interesting probe compounds, and his continuing collaboration is recognized by his continuing status as a Remote Associate Researcher of the Broad Institute Chemical Biology Program. Stefan Kubicek started at CeMM in August 2010 and funding of this EPICAL proposal will allow to further integrate his career in the European research space.
Original text from CORDIS.
Participants
- CEMM - FORSCHUNGSZENTRUM FUER MOLEKULARE MEDIZIN GMBH · WienCoordinatorAustria
Links
Data: CORDIS, © European Union