FoxO suppresses endoplasmic reticulum stress to inhibit growth of Tsc1-deficient tissues under nutrient restriction
Avantika Gupta1, Hugo Stocker1
1Institute of Molecular Systems Biology, ETH Zürich, Zürich, Switzerland.
Abstract:
The transcription factor FoxO has been shown to block proliferation and progression in mTORC1-driven tumorigenesis but the picture of the relevant FoxO target genes remains incomplete. Here, we employed RNA-seq profiling on single clones isolated using laser capture microdissection from Drosophila larval eye imaginal discs to identify FoxO targets that restrict the proliferation of Tsc1-deficient cells under nutrient restriction (NR). Transcriptomics analysis revealed downregulation of endoplasmic reticulum-associated protein degradation pathway components upon foxo knockdown. Induction of ER stress pharmacologically or by suppression of other ER stress response pathway components led to an enhanced overgrowth of Tsc1 knockdown tissue. Increase of ER stress in Tsc1 loss-of-function cells upon foxo knockdown was also confirmed by elevated expression levels of known ER stress markers. These results highlight the role of FoxO in limiting ER stress to regulate Tsc1 mutant overgrowth.
Insights
The transcription factor FoxO limits tumor growth by reducing endoplasmic reticulum (ER) stress. This study identifies FoxO targets that restrict proliferation in Tsc1-deficient cells, revealing a novel role in ER stress regulation.
Area of Science:
- Cell Biology
- Genetics
- Molecular Biology
Background:
- The transcription factor FoxO is known to inhibit proliferation in mTORC1-driven cancers.
- The complete set of FoxO target genes involved in tumorigenesis is not fully understood.
Purpose of the Study:
- To identify FoxO target genes that restrict proliferation in Tsc1-deficient cells under nutrient restriction.
- To elucidate the role of FoxO in regulating endoplasmic reticulum (ER) stress in the context of tumorigenesis.
Main Methods:
- RNA-sequencing (RNA-seq) profiling of single clones from Drosophila larval eye imaginal discs.
- Laser capture microdissection for precise sample isolation.
- Pharmacological induction of ER stress and analysis of ER stress markers.
Main Results:
- Foxo knockdown led to the downregulation of endoplasmic reticulum-associated protein degradation (ERAD) pathway components.
- Increased ER stress, induced pharmacologically or by pathway component suppression, enhanced the overgrowth of Tsc1-deficient tissues.
- Foxo knockdown in Tsc1 loss-of-function cells elevated the expression of known ER stress markers.
Conclusions:
- FoxO plays a critical role in limiting ER stress.
- FoxO regulates Tsc1 mutant overgrowth, at least in part, by modulating ER stress levels.
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