HSF1 deficiency and impaired HSP90-dependent protein folding are hallmarks of aneuploid human cells

Area of Science:

• Cell Biology
• Cancer Research
• Molecular Biology

Background:

• Aneuploidy, characterized by abnormal chromosome numbers, is a hallmark of cancer, linked to malignancy and poor prognosis.
• Aneuploidy is known to inhibit proliferation, alter gene and protein expression, and disrupt cellular proteostasis.
• The precise molecular mechanisms behind aneuploidy-induced gene expression changes and proteostasis impairment remain unclear.

Purpose of the Study:

• To investigate the molecular mechanisms by which aneuploidy disrupts cellular proteostasis.
• To identify the role of heat shock protein 90 (HSP90) and heat shock factor 1 (HSF1) in aneuploid cells.
• To determine if HSF1 activity is compromised in aneuploidy and if its restoration can mitigate aneuploidy-associated phenotypes.

Main Methods:

• Analysis of protein folding capacity in human aneuploid cells.
• Assessment of heat shock response induction and heat shock factor 1 (HSF1) activity.
• Experimental manipulation of HSF1 levels in aneuploid cells to observe effects on HSP90 expression and protein folding.
• Investigation of the impact of impaired protein folding on gene expression.

Main Results:

• Human aneuploid cells exhibit impaired HSP90-mediated protein folding.
• Aneuploidy compromises the induction of the heat shock response, indicating compromised HSF1 activity.
• Increased HSF1 levels counteract aneuploidy's effects on HSP90 expression and protein folding, identifying HSF1 overexpression as an aneuploidy-tolerating mechanism.
• Deficient protein folding capacity directly influences gene expression patterns in aneuploid cells.

Conclusions:

• Impaired HSF1 activity is a critical factor underlying the phenotypes associated with aneuploidy.
• Restoring HSF1 function can rescue protein folding defects in aneuploid cells.
• This study provides mechanistic insights into disturbed proteostasis in aneuploid cells and highlights HSF1's role in cytoprotection and carcinogenesis.