Journal
AUTOPHAGY
Volume 13, Issue 10, Pages 1790-1791Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2017.1349581
Keywords
acetyl-CoA; ACSS2; AMPK; autophagy; lysosomal biogenesis; nucleus; phosphorylation; TFEB; tumor development
Categories
Funding
- National Institute of Neurological Disorders and Stroke [1R01 NS089754]
- National Cancer Institute [1R01CA204996, 2R01 CA109035, 1R01 CA169603]
- NATIONAL CANCER INSTITUTE [R01CA169603] Funding Source: NIH RePORTER
Ask authors/readers for more resources
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 5 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available