My overarching goal is to investigate the importance of protein post-translational modification (PTM) networks in cancer. The signaling system defined by the PTM lysine methylation has recently emerged as a potential key regulator of cancer pathways. However, the mechanisms by which protein lysine methyltransferase (PKMT) enzymes contribute to cancer are poorly understood. I believe that characterizing novel PKMTs involved in the post-translational control of cellular proteins in cancer-relevant signaling networks can provide novel insights into the basic mechanisms of cellular transformation and identify new therapeutic targets for cancer treatment. SETD6 is a PKMT whose expression is dramatically down-regulated in a wide range of human cancers. During my postdoctoral work, we identified SETD6 as a key regulator of proliferation processes by modulating the NFKB signaling pathway and deciphered the molecular mechanism for this regulation. However, knowledge of the overall mode of action of SETD6 in cancer cells and of additional endogenous substrates of this enzyme is still obscure. The working hypothesis is that SETD6 methylation of key cellular substrates modulates cancer pathology. In this research I plan to utilize cellular, biochemical, genomic and a novel proteomic experimental platform I developed to elucidate the role of SETD6 in oncogenic processes and its involvement in the modulation of cellular signaling pathways linked to cancer; to characterize new methylation events catalyzed by SETD6; to understand how these marks are generated and under which specific physiological conditions; to elucidate how these marks are sensed by other cellular factors; and to decipher the molecular mechanisms that transduce these signals. I believe that this work will provide significant insight into the role of SETD6 in the modulation of oncogenic signaling processes with a long term plan to translate this knowledge into therapeutic applications in the future.