Abstract
Cancer encompasses a range of severe diseases characterized by uncontrolled cell growth and the potential for metastasis. Understanding the mechanism underlying tumorigenesis has been a central focus of cancer research. Self-propagating protein aggregates, known as prions, are linked to various biological functions and diseases, particularly those related to mammalian neurodegeneration. However, it remains unclear whether prion-like mechanisms contribute to tumorigenesis and cancer. Using a combined approach of algorithmic predictions, alongside genetic and biochemical experimentation, we identified numerous cancer-associated proteins prone to aggregation, many of which contain prion-like domains (PrLDs). These predictions were experimentally validated for both aggregation and prion-formation. We demonstrate that several PrLDs undergo nucleation-limited amyloid formation, which can alter protein activity in a mitotically heritable fashion. These include SSXT, a subunit of the chromatin-remodeling BAF (hSWI/SNF) complexes; CLOCK, a core component of the circadian clock; and EPN4, a clathrin-interacting protein involved in protein trafficking between the trans-Golgi network and endosomes. The prions formed by these PrLDs occurred in multiple variants and depended on Hsp104, a molecular chaperone with disaggregase activity. Our results reveal an inherent tendency for prion-like aggregation in human cancer-associated proteins, suggesting a potential role for such aggregation in the epigenetic changes driving tumorigenesis.
Original language | English (US) |
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Pages (from-to) | 154-168 |
Number of pages | 15 |
Journal | Molecular and cellular biology |
Volume | 45 |
Issue number | 4 |
DOIs | |
State | Published - 2025 |
Funding
This work was supported by the American Cancer Society (RSG-19-217-01-CCG) to RH and (ABOA Impact RSG-22-086-01-TBE) to MLM, U.S. National Science Foundation, United States (MCB 2332782) to LL, U.S. National Institute of Health (R01GM130927) to RH, (R01GM126318 and R01GM155872) to ZD and (1R01GM144617-01) to MLM.
Keywords
- Prion
- aggregation
- cancer
- prion-like domain (PrLD)
- yeast
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology