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Published on: January 31, 2025
Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity
Ying Zhao1, Jing Yang, Wenjuan Liao
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China.
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.
Insights
Cytosolic Forkhead O1 (FoxO1) protein mediates autophagy, a cellular process crucial for tumor suppression. This mechanism involves FoxO1 acetylation and interaction with Atg7, leading to cancer cell death and demonstrating FoxO1
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Autophagy degrades cellular components but its role in tumor suppression is unclear.
- Forkhead O (FoxO) proteins are implicated in various cellular processes, including stress response and cancer.
Purpose of the Study:
- To investigate the role of cytosolic Forkhead O1 (FoxO1) in mediating autophagy.
- To elucidate the mechanism by which FoxO1 influences autophagy and its connection to tumor suppression.
Main Methods:
- Utilized human cancer cell lines and a xenograft mouse model.
- Investigated endogenous FoxO1 requirement for autophagy under oxidative stress and serum starvation.
- Analyzed FoxO1 acetylation, its dissociation from sirtuin-2 (SIRT2), and its binding to Atg7.
Main Results:
- Endogenous FoxO1 is essential for autophagy induction in cancer cells.
- FoxO1's role in autophagy is independent of its transcriptional activity.
- Stress-induced FoxO1 acetylation and subsequent binding to Atg7 modulate autophagy, promoting cell death.
- FoxO1-mediated cell death exhibits tumor suppressor activity in preclinical models.
Conclusions:
- Cytosolic FoxO1 acts as a key mediator of autophagy.
- FoxO1's interaction with SIRT2 and Atg7 links autophagy to cancer cell death.
- This pathway highlights the anti-neoplastic activity of FoxO1 and its connection to autophagy, offering potential therapeutic insights.
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