KAT8-catalyzed lactylation contributes to eEF1A2-mediated protein synthesis and colorectal carcinogenesis

Abstract As an emerging metabolite-mediated post-translational modification, lysine lactylation (Kla) is discovered on histones that regulates gene transcription from chromatin. However, whether lactylation could occur outside the nucleus across broad proteins and its regulatory enzymes remains unclear. Here, we observe global Kla occurs in both nucleus and cytoplasm in colorectal cancer (CRC), and negatively correlates with its prognosis. Among the lactylated proteins in CRC, we find eEF1A2, a fundamental protein in translation elongation, is hyperlactylated at its lysine 408 (K408). The lactylation of eEF1A2K408 results in increased translation elongation rates and elevated protein synthesis in line with CRC cells proliferation. By screening eEF1A2 interacted proteins, we identify KAT8 as a pan-Kla writer which is responsible for installing Kla on many proteins in diverse biological processes, notably in tumorigenic signaling pathways. Deletion of KAT8 effectively decreases CRC tumor growth especially in high-lactic tumor microenvironment, which associates with reduced KAT8-mediated Kla. Together, our work uncovers that KAT8 catalyzes broad lactylation as a lactyltransferase which could be a potential target for CRC and the KAT8-eEF1A2 Kla axis is a novel mechanism for cancer adaptation to increased translational requirements.