Overexpression of the MYC protein is oncogenic and commonly observed in cancer, and its inhibition induces regression of tumors in animal models. Hence, MYC is considered a promising target for cancer treatment. Besides overexpression, MYC can be deregulated by additional mechanisms, including aberrant upstream signaling pathways and posttranslational modifications (PTMs), such as phosphorylation, ubiquitination, sumoylation and acetylation that may affect the turnover and activity of the MYC protein. In particular, the functions of MYC acetylation in normal and cancer cells have remained elusive and the current information is scarce and often controversial. We propose that the limited progress and apparent discrepancies are due, in part, to (i) the fact that different histone acetyltransferases (HATs) and deacetylases (HDACs) dynamically remodel the acetyl marks on distinct lysine (K) residues of MYC in different contexts and with different outcomes, (ii) the use of pan-acetyl-lysine antibodies that do not distinguish MYC acetylation at different K residues, and (iii) the study of a limited number of in vitro cell systems/conditions that often involve artificial overexpression of HATs and may not model the signaling mechanisms leading to MYC acetylation endogenously in normal cellular contexts or in tumor cells. Hence, the relevance of MYC acetylation to normal cell biology and/or cancer development has remained largely unknown. Our laboratory has identified distinct K residues of MYC that are acetylated by different HATs and are important for specific MYC functions in selective gene regulation and transformation of rodent fibroblasts. We hypothesize that MYC acetylation is under tight regulatory control in normal cells but is deregulated in tumor-derived cancer cells and influences the oncogenic/transformation activity of MYC in human cells. To test this, Aim1 will determine whether MYC acetylation is deregulated in cancer cells by analyzing a panel of normal and cancer cell lines with acetyl-lysine site-specific antibodies and will identify specific histone deacetylase pathways that may influence site-specific MYC acetylation.
Aim 2 will investigate the function of specific acetyl-lysine residues in MYC-dependent transformation of human cells and in the maintenance of the transformed phenotype of tumor-derived cancer cells. This project may uncover for the first time a deregulated acetylation of MYC at specific residues in cancer cells and establish the role of these acetylated residues in MYC-dependent transformation of human cells.
Many cancers develop as a result of an excessive production or deregulated activity of the MYC oncoprotein, a promising therapeutic target. MYC activity can be deregulated by aberrant chemical modifications of the protein. Since we discovered lysine acetylation as a new modification of MYC, this project investigates the possibility that MYC acetylation is deregulated in cancer cells and contributes to MYC ability to transform normal cells into tumor cells.
