HSF 1 deficiency and impaired HSP 90‐dependent protein folding are hallmarks of aneuploid human cells

Aneuploidy is a hallmark of cancer and is associated with malignancy and poor prognosis. Recent studies have revealed that aneuploidy inhibits proliferation, causes distinct alterations in the transcriptome and proteome and disturbs cellular proteostasis. However, the molecular mechanisms underlying the changes in gene expression and the impairment of proteostasis are not understood. Here, we report that human aneuploid cells are impaired in HSP 90‐mediated protein folding. We show that aneuploidy impairs induction of the heat shock response suggesting that the activity of the transcription factor heat shock factor 1 ( HSF 1) is compromised. Indeed, increased levels of HSF 1 counteract the effects of aneuploidy on HSP 90 expression and protein folding, identifying HSF 1 overexpression as the first aneuploidy‐tolerating mutation in human cells. Thus, impaired HSF 1 activity emerges as a critical factor underlying the phenotypes linked to aneuploidy. Finally, we demonstrate that deficient protein folding capacity directly shapes gene expression in aneuploid cells. Our study provides mechanistic insight into the causes of the disturbed proteostasis in aneuploids and deepens our understanding of the role of HSF 1 in cytoprotection and carcinogenesis.