Summary
Polycomb repressive complex 2 (PRC2), which incorporates repressive methyl-lysine marks on histone H3 to facilitate global transcriptional repression, is an integral epigenetic modifier in normal development. Components of this complex, especially EZH2, are hyperactive or overexpressed in a broad range of cancers, resulting in excessive silencing of tumor suppressor genes (TSGs). Moreover, cancers with defects in the SWI/SNF complex, the most frequently mutated chromatin regulatory complex in cancer, are dependent on PRC2 function for survival. While inhibition or degradation of PRC2 components have become extremely attractive approaches to cancer therapy, they still suffer from suboptimal kinetics and perturbation because they must rely on opposing epigenetic modifiers and transcriptional regulators to derepress expression of silenced TSGs. Thus, I aim to overcome this issue by leveraging the cancer driver itself to derepress silenced TSGs. In this regard, I will utilize a high-throughput protein recruitment screen, coupled to next-generation sequencing, to identify proteins (effectors) that, when recruited to PRC2, can rewire its function to directly derepress a PRC2-silenced locus. This screen will be used a base to develop novel proximity inducing compounds, which can rewire the function of PRC2. The compound that produces the strongest transcriptional derepression and anti-proliferative effects in cancer cells will then be characterized via transcriptomics, and chromatin profiling to determine its effects on endogenous gene expression. Ultimately, this study will establish a new class of PRC2 targeting compounds that will pave the way for improved cancer therapies, which both inhibit PRC2 methyltransferase activity and directly derepress PRC2-silenced TSGs.
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| Web resources: | https://cordis.europa.eu/project/id/101153103 |
| Start date: | 01-07-2025 |
| End date: | 30-06-2027 |
| Total budget - Public funding: | - 199 440,00 Euro |
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Original description
Polycomb repressive complex 2 (PRC2), which incorporates repressive methyl-lysine marks on histone H3 to facilitate global transcriptional repression, is an integral epigenetic modifier in normal development. Components of this complex, especially EZH2, are hyperactive or overexpressed in a broad range of cancers, resulting in excessive silencing of tumor suppressor genes (TSGs). Moreover, cancers with defects in the SWI/SNF complex, the most frequently mutated chromatin regulatory complex in cancer, are dependent on PRC2 function for survival. While inhibition or degradation of PRC2 components have become extremely attractive approaches to cancer therapy, they still suffer from suboptimal kinetics and perturbation because they must rely on opposing epigenetic modifiers and transcriptional regulators to derepress expression of silenced TSGs. Thus, I aim to overcome this issue by leveraging the cancer driver itself to derepress silenced TSGs. In this regard, I will utilize a high-throughput protein recruitment screen, coupled to next-generation sequencing, to identify proteins (effectors) that, when recruited to PRC2, can rewire its function to directly derepress a PRC2-silenced locus. This screen will be used a base to develop novel proximity inducing compounds, which can rewire the function of PRC2. The compound that produces the strongest transcriptional derepression and anti-proliferative effects in cancer cells will then be characterized via transcriptomics, and chromatin profiling to determine its effects on endogenous gene expression. Ultimately, this study will establish a new class of PRC2 targeting compounds that will pave the way for improved cancer therapies, which both inhibit PRC2 methyltransferase activity and directly derepress PRC2-silenced TSGs.Status
SIGNEDCall topic
HORIZON-MSCA-2023-PF-01-01Update Date
25-11-2024
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