Cancer-testis antigens are a family of tumor specific proteins that are typically expressed in the male germline and then aberrantly expressed in many cancers. Melanoma Antigen Genes (MAGEs) are the largest family of cancer-testis antigens and are divided into Type I and Type II MAGEs based on expression pattern. Type I MAGEs are true cancer testis antigens and their expression in tumors is often associated with poor patient prognosis. While cancers often express more than one Type I MAGE gene, this study focusses on MAGEB2, an exemplary member of the Type I gene family and therefor a bona fide cancer-testis antigen. There is a significant gap in understanding the mechanisms that regulate expression of MAGEB2, and the role that aberrantly expressed MAGEB2 plays in cellular transformation. We hypothesized that epigenetic mechanisms such as DNA methylation, which regulates the expression of many germline genes also regulates MAGEB2 gene expression. Using bioinformatics and ChIP assays, we have determined the transcription factor networks that regulate MAGEB2 expression. In addition, we show that expressing MAGEB2 gene provides non-transformed cells with a proliferative advantage by dampening TGFb signaling. Taken together our data indicate that cells use epigenetic memory to express MAGEB2 resulting in shift of the cells’ gene signature to a pro-proliferative, anti-apoptotic state that firmly places cells in the path to transformation.