Histone acetyl transferase MOF orchestrates outcomes at the crossroad of oncogenesis, DNA damage response, proliferation, and stem cell development

The DNA and protein complex known as chromatin is subject to post-translational modifications (PTMs), which regulate cellular functions, such that PTM dysregulation can lead to disease including cancer. One critical PTM is acetylation/deacetylation, which is being investigated as a means to develop targeted cancer therapies. The histone acetyl transferase (HAT) family of proteins perform histone acetylation. In humans, MOF (hMOF), a member of the MYST family of HATs, acetylate histone H4 at lysine 16 (H4K16ac). MOF-mediated acetylation plays a critical roles in the DNA damage response (DDR) and embryonic stem cell development. Functionally, MOF is found in two distinct complexes NSL in humans (Non Specific Lethal) and MSL (Male Specific Lethal) in flies. NSL complex is also being able to acetylate additional histone H4 sites. Dysregulation of MOF activity occurs in multiple cancers including ovarian, medulloblastoma, breast, colorectal and lung cancer. Bioinformatics analysis of KAT8, the gene encoding hMOF, indicated it is highly overexpressed in kidney tumors as part of a concerted gene co-expression program that would support high levels of chromosome segregation and cell proliferation. The linkage between MOF and tumor proliferation suggests there are additional functions of MOF that remain to be discovered.