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Local histone acetylation by ACSS2 promotes gene transcription for lysosomal biogenesis and autophagy.
Autophagy 2017 October 4
Overcoming metabolic stress is a critical step in tumorigenesis. Acetyl coenzyme A (acetyl-CoA) converted from glucose or acetate is a substrate used for histone acetylation to regulate gene expression. However, how acetyl-CoA is produced under nutritional stress conditions is unclear. Herein we report that nutritional stress induces nuclear translocation of ACSS2 (acyl-CoA synthetase short-chain family member 2). This translocation is mediated by AMP-activated protein kinase (AMPK)-dependent ACSS2 Ser659 phosphorylation and subsequent exposure of the nuclear localization signal of ACSS2 to KPNA1/importin α5 for binding. In the nucleus, ACSS2 forms a complex with TFEB (transcription factor EB) and utilizes the acetate generated from histone deacetylation to locally produce acetyl-CoA for histone acetylation in the promoter regions of TFEB target genes. Knock-in of nuclear translocation-deficient or inactive ACSS2 mutants in glioblastoma cells abrogates glucose deprivation-induced lysosomal biogenesis and autophagy, reduces cell survival, inhibits brain tumorigenesis, and enhances the inhibitory effect of the glucose metabolism inhibitor 2-deoxy-d-glucose on tumor growth. These results reveal a novel biologic role for ACSS2 in recycling of nuclear acetate for histone acetylation to promote lysosomal and autophagy-related gene expression and counteract nutritional stress, highlighting the importance of ACSS2 in maintaining autophagy and lysosome-mediated cellular energy homeostasis during tumor development.
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