Anti-neoplastic activity of the cytosolic FoxO1 results from autophagic cell death.
Although Beclin 1 and mTOR are considered to be the main molecules to modulate the autophagic process, searching for other autophagy-regulating molecules is still an ongoing challenge to scientists. Here we demonstrated that FoxO1, a forkhead O family protein, is a mediator of autophagy. Upon oxidative stress or serum starvation, endogenous FoxO1 was required for autophagy in human cancer cell lines, and this process was independent of FoxO1's transcriptional activity as well as mTOR or Beclin 1. In response to stress, FoxO1 dissociated from an NAD(+)-dependent histone deacetylase SIRT2 and FoxO1 thus became acetylated and in turn bound to Atg7, an E1-like protein, to influence the autophagic process leading to cell death. In particular, cytosolic FoxO1 suppressed tumor xenograft growth in nude mice in an autophagy-dependent manner. Our studies provide evidence that cytosolic FoxO1-induced autophagy is associated with tumor suppression function.
Zhao
Ying
Y
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Sciences Center, Beijing, China.
Wang
Lina
L
Yang
Jing
J
Zhang
Ping
P
Ma
Ke
K
Zhou
Jingyi
J
Liao
Wenjuan
W
Zhu
Wei-Guo
WG
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001343:Autophagy / Q000502:physiology*; D000071193:Autophagy-Related Protein 7; D045744:Cell Line, Tumor; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics / Q000378:metabolism
D000970:Antineoplastic Agents; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D011993:Recombinant Fusion Proteins; C474199:SIRT2 protein, human; D056565:Sirtuin 2; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes