Project Summary Dynamic acetylation/deacetylation of histones and nonhistone proteins is a critical switch in gene regulation. Manipulation of the acetylation switch is emerging as a promising therapeutic strategy in the treatment of cancer. My laboratory has a long-term interest in clarifying the functions, mechanisms of action, and regulation of lysine acetyltransferases and deacetylases, exploring their roles in diseases, and using the resulting knowledge to develop new and better strategies for the treatment of diseases such as cancer. The key focus of this resubmission application is on the Males Absent on the First (MOF, also called KAT8 or MYST1) protein, a member of the MYST lysine acetyltransferase family. MOF regulates a variety of cellular processes including gene transcription, DNA damage responses, and embryonic development. The proposed project is significant because although increasing evidence suggests that MOF is also closely involved in cancer, the exact mechanism by which MOF impacts tumor development and progression is unclear. Our preliminary studies revealed an unexpected function of MOF in the transcriptional repression of epithelial to mesenchymal transition (EMT) and cytokine genes in lung cancer. Furthermore, MOF depletion significantly affects lung tumorigenesis in mouse models due to release of its transcriptional repression. Based on these exciting preliminary results, we hypothesize that MOF may be a potential target for treatments of lung cancer. The long-term objective is to explore how MOF regulates uncharacterized gene expression and signaling processes to impact lung cancer. The central hypothesis will be tested by pursuing three specific aims: 1) Dissect the novel and unexpected mechanisms by which MOF represses gene transcription; 2) Examine how MOF controls gene expression via the methyltransferase G9a and TGF-beta/SMAD; and 3) Explore the implications of SIRT1-mediated deacetylation of MOF in lung cancer development. The expected outcome of this work will help elucidate new functions of MOF and its mechanisms of action in lung tumorigenesis, and provide insights into future development of new therapeutic strategies for lung cancer.