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Investigating the role of the epigenetic regulator PRDM6 in cancer
thesisposted on 10.09.2021, 13:45 by Mohamed Hassan
PRDM6 belongs to PRDM family of proteins, which function both as transcription factors and epigenetic regulators to mediate differentiation and maturation events that act in a wide range of developmental processes. As such, most PRDM family members are known or suspected oncogenes or tumour suppressors, and have been implicated in a wide range of cancers and other human pathologies. The involvement of PRDM6 in cancer was first highlighted through the discovery of a rare but a recurrent translocation involving IGH in patients diagnosed with diffuse large B-cell Lymphoma (DLBCL), indicating a potential role for PRDM6 to function as a driver for this subtype of lymphoma. More recently, a large-scale genomic study of medulloblastoma (MB) revealed PRDM6 to be the most frequently altered gene in a poorly defined subtype of MB. This thesis is the first to study the function of PRDM6 in cancer. The overexpression of PRDM6 in primary NIH/3T3 fibroblast and LP-9 mesothelial cells resulted in a host of oncogenic transformations in vitro. Microarray analysis of transformed NIH-3T3 cells shows a huge change in the gene expression profiles of these cells, involving differential expression of a large number of genes with diverse biological functions. Conversely, the expression of PRDM6 in lung cancer is beneficial, as depletion in H1299 lung adenocarcinoma tissue results in downregulation of a number of tumour suppressor and an impaired DNA repair capacity. The role of PRDM6 in cancer could be driven by its epigenetic capabilities. The presence of a PR/SET domain in PRDM6 implies that it functions as an epigenetic regulator. Using a peptide array containing all known histone modifications, we show that PRDM6 preferentially binds acetylated histones H4 residues, indicating that PRDM6 potentially serves as a histone code reader.