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Published on: May 28, 2021
DAF-16/FOXO targets genes that regulate tumor growth in Caenorhabditis elegans
Julie Pinkston-Gosse1, Cynthia Kenyon
1Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, California 94158, USA.
Abstract:
Cancer is an age-related disease, and inhibiting insulin/insulin-like growth factor 1 (IGF-1) signaling extends lifespan and increases tumor resistance in C. elegans and mammals. To investigate how the insulin/IGF-1 pathway couples these two processes, we analyzed putative transcriptional targets of the C. elegans FOXO transcription factor DAF-16, which promotes both longevity and tumor resistance. Twenty-nine of 734 genes tested influenced germline-tumor cell proliferation or p53-dependent apoptosis. About half of these genes also affected normal aging, thereby linking these two processes mechanistically. Many of these 29 genes are orthologs of known human tumor suppressors or oncogenes, suggesting that others may be as well. Our findings implicate nuclear-pore modification in p53-dependent cell death, because inhibiting nuclear-pore genes that are upregulated by DAF-16 blocks p53-dependent cell death in the tumor, but not normal, p53-independent, germline cell death.
Insights
Inhibiting insulin/insulin-like growth factor 1 (IGF-1) signaling extends lifespan and enhances tumor resistance. This study identifies genes linking aging and cancer, including nuclear-pore genes affecting cell death.
Area of Science:
- Gerontology
- Molecular Biology
- Cancer Research
Background:
- Cancer is strongly associated with aging.
- The insulin/insulin-like growth factor 1 (IGF-1) pathway influences both aging and cancer development.
- The FOXO transcription factor DAF-16 is a key regulator of longevity and tumor suppression.
Purpose of the Study:
- To elucidate the molecular mechanisms by which the insulin/IGF-1 pathway links aging and cancer resistance.
- To identify transcriptional targets of DAF-16 that regulate tumor cell proliferation and apoptosis.
- To investigate the role of these targets in normal aging processes.
Main Methods:
- Analysis of putative transcriptional targets of the C. elegans FOXO transcription factor DAF-16.
- Functional screening of 734 genes for effects on germline-tumor cell proliferation and p53-dependent apoptosis.
- Assessment of gene influence on normal aging in C. elegans.
Main Results:
- Twenty-nine of 734 tested genes significantly affected germline-tumor cell proliferation or p53-dependent apoptosis.
- Approximately half of these 29 genes also influenced normal aging, establishing a mechanistic link.
- Many identified genes are orthologs of known human tumor suppressors or oncogenes.
- Nuclear-pore genes upregulated by DAF-16 were found to modulate p53-dependent cell death in tumors.
Conclusions:
- The insulin/IGF-1 pathway mechanistically links aging and cancer resistance through shared transcriptional targets.
- DAF-16 regulates genes involved in both tumor suppression and normal aging.
- Nuclear-pore modification plays a role in p53-dependent tumor cell death, distinct from normal cell death pathways.
