Investigating the role of the epigenetic regulator PRDM6 in cancer

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.