The function of CBP/p300 and BET-proteins in dependence of H3.3K27M mutation in diffuse intrinsic pontine glioma (DIPG)

Diffuse intrinsic pontine gliomas (DIPG) represent the most aggressive pediatric high grade brain tumor entity with fatal prognosis. 85 % of all DIPG carry a mutation in one of the Histone 3 genes (H3K27M) leading to hypotrimethylation of H3K27 and simultaneous hyperacetylation. Accordingly, it becomes highly suggestive that the H3K27 histone acetyltransferase CREB binding protein (CBP) & p300 and the histone acetylation- “reading” Bromodomain and Extra-terminal domain (BET) proteins play a tumor-promoting role in H3K27M-mutated DIPG. To investigate their function, siRNA-mediated knockdown of these proteins is performed in isogenic DIPG cell lines carrying H3K27M or H3WT and subsequent functional and molecular biological assays have been performed to determine the differential impact of CBP/p300 and BET-proteins in dependence of the H3 mutation status. Preliminary results reveal that CBP knockdown had the strongest effects on tumor-biological features in comparison to knockdown of the BET-proteins. In conclusion, H3K27M-mutated DIPG appear to markedly stronger depend on CBP than on p300 or BET proteins.

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Artikel online veröffentlicht:
13. Mai 2020