O-GlcNAcylation of ATP-citrate lyase couples glucose supply to lipogenesis for rapid tumor cell proliferation

Cancer cells are characterized by a high rate of fatty acid synthesis required for membrane expansion during rapid proliferation. As a key rate-limiting enzyme in de novo fatty acid synthesis, ACLY is frequently deregulated by PTMs in tumors. Despite recently identified O-GlcNAcylation on ACLY, its biological function is still unknown. Here we identify ACLY S979 as a key O-GlcNAcylation site that is crucial for ACLY function. By improving CoA association, S979 O-GlcNAcylation enhances ACLY activity and in turn promotes lipogenesis and tumor cell proliferation. Also, it is capable of sensing nutritional alterations and EGF stimulation and finetunes fatty acid synthesis accordingly. Together, this work brings insights into the dynamic coordination between glucose supply and lipogenesis for rapid tumor cell proliferation.