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Metabolic Regulator IAPP (Amylin) Is Required for BRAF and RAS Oncogene-Induced Senescence
Sam Garnett1, Angeline de Bruyns1, Veronique Provencher-Tom1
1Department of Biology, McGill University, Montréal QC, Canada.
Molecular Cancer Research : MCR
|January 27, 2021
Summary
Islet amylin polypeptide (IAPP) prevents oncogene-induced senescence (OIS) by altering cell metabolism and chromatin. Restoring IAPP reactivates OIS, suggesting IAPP analogs could treat BRAF/RAS mutant cancers.
Area of Science:
- Cellular biology
- Metabolism
- Oncology
Background:
- Cellular senescence is a key tumor suppressor mechanism against oncogenic signals.
- Senescence involves cell-cycle arrest, altered morphology, and metabolic changes.
- Oncogene-induced senescence (OIS) is crucial for preventing cancer progression.
Purpose of the Study:
- To identify genes regulating proliferation under sustained oncogene signaling.
- To investigate the role of islet amylin polypeptide (IAPP) in OIS.
- To explore IAPP's metabolic and chromatin regulatory functions in OIS.
Main Methods:
- Conducted an shRNA-based genetic screen in primary cells with inducible BRAF.
- Depleted IAPP and analyzed its effects on OIS in human cells.
- Examined metabolomic and chromatin modification changes upon IAPP depletion.
Main Results:
- IAPP depletion prevented RAS and BRAF oncogene-induced senescence (OIS).
- IAPP depletion caused metabolic reprogramming and widespread chromatin alterations.
- Exogenous amylin treatment restored OIS in IAPP-depleted cells.
Conclusions:
- IAPP is a novel metabolic regulator of OIS.
- IAPP's metabolic role is linked to chromatin modifications during senescence.
- IAPP analogs may offer therapeutic potential for BRAF/RAS mutant cancers by inducing senescence.
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