hMOF and associated proteins in transcription and cancer

Abstract

The lysine acetyltransferase MOF (males absent on the first) has been associated with transcriptional activation in Drosophila melanogaster. This activation is mediated by its acetylation of histone H4 at lysine 16 (H4K16ac). The human orthologue of MOF (hMOF) has been reported to be part of at least two distinct complexes; the hMSL (male-specific lethal) and the hNSL (non-specific lethal) complex. Here, the role of hMOF containing complexes in the regulation of gene expression was elucidated by establishing an in vivo transcription reporter assay. Using this system, it was found that whilst hMOF itself has a two-fold activating effect on transcription, the associated hMSL1 protein promotes transcriptional repression of the reporter gene. Expression of hMOF and acetylation of H4K16 are frequently lost or decreased in a variety of human cancers. Here, the role of hMOF in cancer was investigated by generating immortal human fibroblasts with reduced levels of the hMOF protein to mimic the loss of hMOF seen in cancer. The phenotype of these cells was examined and it was found that loss of hMOF predisposed the cells to become polyploid, a phenomenon that is often linked with transformation. Counting the chromosomes in these cells showed the chromosome number to be near tetraploidy. Two common causes of polyploidy are mitotic slippage or endoreplication. Analysis of hMOF and hMSL genes¿ expression was measured over the cell cycle and it was found that their expression peaks during S phase. Live-cell imaging was attempted in order to elucidate which defect loss of hMOF expression triggered. The nuclear volume doubled overtime consistent with polyploidy. However, no mitotic defects were observed. Together with the expression profile this possibly indicates a replication defect rather than mitotic slippage as the cause of the polyploidy. In summary, these studies imply a role of hMOF and its associated proteins in transcription, replication and cancer.