Investigating the Aggregation and Prionogenic Properties of Human Cancer-Related Proteins

Dustin Goncharoff, Zhiqiang Du, Shriram Venkatesan, Brandon Cho, Jenny Zhao, Milad J. Alasady, Dalton Huey, Hannah Ma, Jake Rosenthal, Alexander Turenitsa, Coral Feldman, Randal Halfmann, Marc L. Mendillo*, Liming Li

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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 languageEnglish (US)
Pages (from-to)154-168
Number of pages15
JournalMolecular and cellular biology
Volume45
Issue number4
DOIs
StatePublished - 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

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