Overcoming metabolic stress is a critical step in tumor growth. Acetyl coenzyme A (acetyl-CoA) generated from glucose and acetate uptake is important for his-tone acetylation and gene expression. However, how acetyl-CoA is produced under nutritional stress is un-clear. We demonstrate here that glucose deprivation results in AMP-activated protein kinase (AMPK)-medi-ated acetyl-CoA synthetase 2 (ACSS2) phosphoryla-tion at S659, which exposed the nuclear localization signal of ACSS2 for importin a5 binding and nuclear translocation. In the nucleus, ACSS2 binds to tran-scription factor EB and translocates to lysosomal and autophagy gene promoter regions, where ACSS2 incorporates acetate generated from histone acetylation turnover to locally produce acetyl-CoA for histone H3 acetylation in these regions and pro-mote lysosomal biogenesis, autophagy, cell survival, and brain tumorigenesis. In addition, ACSS2 S659 phosphorylation positively correlates with AMPK ac-tivity in glioma specimens and grades of glioma malig-nancy. These results underscore the significance of nuclear ACSS2-mediated histone acetylation in main-taining cell homeostasis and tumor development.
