Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity

Nat Cell Biol. 2010 Jul;12(7):665-75. doi: 10.1038/ncb2069. Epub 2010 Jun 13.

Abstract

Autophagy is characterized by the sequestration of bulk cytoplasm, including damaged proteins and organelles, and delivery of the cargo to lysosomes for degradation. Although the autophagic pathway is also linked to tumour suppression activity, the mechanism is not yet clear. Here we report that cytosolic FoxO1, a forkhead O family protein, is a mediator of autophagy. Endogenous FoxO1 was required for autophagy in human cancer cell lines in response to oxidative stress or serum starvation, but this process was independent of the transcriptional activity of FoxO1. In response to stress, FoxO1 was acetylated by dissociation from sirtuin-2 (SIRT2), a NAD(+)-dependent histone deacetylase, and the acetylated FoxO1 bound to Atg7, an E1-like protein, to influence the autophagic process leading to cell death. This FoxO1-modulated cell death is associated with tumour suppressor activity in human colon tumours and a xenograft mouse model. Our finding links the anti-neoplastic activity of FoxO1 and the process of autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Actins / genetics
  • Actins / metabolism
  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Animals
  • Autophagy / drug effects*
  • Autophagy-Related Protein 7
  • Blotting, Western
  • Cell Line, Tumor
  • Cytosol / drug effects
  • Cytosol / metabolism*
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • HeLa Cells
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Mice
  • Mice, Nude
  • Microtubule-Associated Proteins / genetics
  • Microtubule-Associated Proteins / metabolism
  • Protein Binding
  • RNA Interference
  • Sequestosome-1 Protein
  • Sirtuin 2 / genetics
  • Sirtuin 2 / metabolism
  • Ubiquitin-Activating Enzymes / genetics
  • Ubiquitin-Activating Enzymes / metabolism

Substances

  • Actins
  • Adaptor Proteins, Signal Transducing
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Microtubule-Associated Proteins
  • SQSTM1 protein, human
  • Sequestosome-1 Protein
  • light chain 3, human
  • Hydrogen Peroxide
  • SIRT2 protein, human
  • Sirtuin 2
  • Atg7 protein, human
  • Autophagy-Related Protein 7
  • Ubiquitin-Activating Enzymes