Epigenetic mechanisms in cancer
Discover and delineate chromatin modifications affecting cancer progression
About the group
Histone modifications such as lysine-methylation of histone H3 by MLL represent an epigenetic mechanism that dynamically affects many chromatin-associated processes including transcription. Chromosomal translocations involving the gene coding for MLL make up approximately 10% of acute leukemias in all age groups with an incidence of 70 to 80% in the case of infant leukemias. The mechanisms by which MLL translocations contribute to leukemogenesis remain unclear. MLL interacts with AKAP95, a protein overexpressed in lung and rectal cancer.
Our previous research results (Lopez-Soop et al, Cell Cycle, 2017) implicate AKAP95 in normal function of the spindle assembly checkpoint (SAC). The SAC is a surveillance mechanism often deregulated in cancer that contributes to faithful chromosome segregation during mitosis and protects the cell against chromosomal instability (CIN, the loss or gain of whole or parts of chromosomes). Despite its prevalence and clinical relevance, a consistent basis for how CIN arises at the molecular level is lacking.
We hypothesize that AKAP95 constitutes a relay platform for the docking of MLL histone methyltransferases and integration with cell signaling pathways to coordinate transcription. We investigate AKAP95-anchored MLL at regulatory sequences of cancer-associated genes, and how MLL complexes anchored by AKAP95 regulate transcription of these cancer-associated genes. We also study the extent to which the roles of AKAP95 in regulating MLL complexes depend on the anchoring of important cell signaling molecules. Finally, we are testing whether the role of AKAP95 in regulating the spindle assembly checkpoint (SAC) is dependent on MLL anchoring
Our results should contribute to the molecular definition of protein complexes involved in epigenetic regulation mechanisms of fundamental importance for cancer progression, but which remain largely uncharacterized at a molecular level. There is an increasing appreciation that targeting epigenetic regulators can be used in a combinatorial therapy approach directed against cancer. This strategy relies on the combination of several small inhibitors to interfere simultaneously with specific histone modifying enzymes and/or the recognition of a modified histone pattern by a chromatin reader protein. This should lead to a multi-pronged targeting approach aiming to disrupt simultaneously several tumor-specific interactions.
- Prof. Eva Bàrtovà (Institute of Biophysics, Brno, Czech Republic)
- Prof. Heidi Kiil Blomhoff (Department of Molecular Medicine, UiO)
- Prof. Philippe Collas (Department of Molecular Medicine, UiO)
- Prof. Mitchell Lazar (University of Pennsylvania, USA)
- Prof. Kjetil Taskèn (Biotechnology Center, Oslo)