Die Rolle von KAT1 und KAT2B in der Melanom-Resistenzentwicklung gegenüber MAPK-Inhibitoren
Zusammenfassung der Projektergebnisse
Histone proteins play a fundamental role in compacting DNA into the nucleus by functioning like a spool that wraps the DNA around them. Each spool is composed of the core histone proteins H2A, H2B, H3 and H4. So-called histone variants are proteins that can substitute for these core histones and confer new, unique structural and functional features to change the expression of genes encoded on nearby DNA. Interestingly, histone variants and the proteins that load them onto the DNA (so-called histone chaperones) are often altered in both paediatric and adult solid tumours. In a previous study, our lab has identified the histone variant H2A.Z as a driver of malignant melanoma, which is a form of skin cancer that begins in the cells (melanocytes) that control the pigment in your skin. H2A.Z is overexpressed in melanoma cells and this overexpression was shown to correlate with poor patient prognosis. Further, the loss of H2A.Z could suppress melanoma cell growth and sensitize the cells for chemotherapy. However, histone variants like H2A.Z.2 are difficult to target, due to their very flat interaction surface that doesn’t offer docking sites for small molecule compounds. Here, we propose a new strategy to specifically target H2A.Z, which is to target the histone chaperones that deposit H2A.Z onto the DNA instead. Deposition of H2A.Z is achieved by either of two multiprotein chaperone complexes: The SRCAP complex or the p400–TIP60 complex. YL1 is a common subunit of both complexes that also directly binds to H2A.Z. In this study, I was able to demonstrate that loss of either SRCAP or YL1 in melanoma cells results in a dramatic depletion of H2A.Z, which in turn results in the suppression of many growth-promoting genes that are usually bound and regulated by H2A.Z. This manifests in growth arrest and cell death of melanoma cells, therefore describing a new epigenetic strategy for melanoma treatment.
