Consequences of Aneuploidy in Cancer: Transcriptome and Beyond

Cancer cells differ from normal healthy cells in multiple aspects ranging from altered cellular signaling through metabolic changes to aberrant chromosome content, so called aneuploidy. The large-scale changes in copy numbers of chromosomes or large chromosomal regions due to aneuploidy alter significantly the gene expression, as several hundreds of genes are gained or lost. Comparison of quantitative genome, transcriptome and proteome data enables dissection of the molecular causes that underlie the gene expression changes observed in cancer cells and provides a new perspective on the molecular consequences of aneuploidy. Here, we will map to what degree aneuploidy affects the expression of genes located on the affected chromosomes. We will also address the effects of aneuploidy on global gene expression in cancer cells as well as whether and how it may contribute to the physiology of cancer cell

Effects of aneuploidy on gene expression: implications for cancer

Unbalanced chromosome content, so-called aneuploidy, is a hallmark of cancer cells. Changes in the copy numbers of chromosomes or large chro- mosomal regions significantly alter the expression of several hundreds of genes that are gained or lost. At the same time, aneuploidy per se affects the transcription of many genes throughout the entire genome, as several pathways are activated or inhibited in response to changes in chromosome copy number. In recent years, a large amount of quantitative genome, tran- scriptome and proteome data has enabled comparison of the changes in gene expression observed in aneuploid cancer cells, as well as in model ane- uploid cells with defined karyotypes. Here, we summarize how aneuploidy shapes gene expression and how it may contribute to the phenotypes of cancer cells

HSF1 deficiency and impaired HSP90-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 HSP90-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 (HSF1) is compromised. Indeed, increased levels of HSF1 counteract the effects of aneuploidy on HSP90 expression and protein folding, identifying HSF1 overexpression as the first aneuploidy-tolerating mutation in human cells. Thus, impaired HSF1 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 HSF1 in cytoprotection and carcinogenesis

Chromosomal instability, tolerance of mitotic errors and multidrug resistance are promoted by tetraploidization in human cells

Up to 80% of human cancers, in particular solid tumors, contain cells with abnormal chromosomal numbers, or aneuploidy, which is often linked with marked chromosomal instability. Whereas in some tumors the aneuploidy occurs by missegregation of one or a few chromosomes, aneuploidy can also arise during proliferation of inherently unstable tetraploid cells generated by whole genome doubling from diploid cells. Recent findings from cancer genome sequencing projects suggest that nearly 40% of tumors underwent whole genome doubling at some point of tumorigenesis, yet its contribution to cancer phenotypes and benefits for malignant growth remain unclear. Here, we investigated the consequences of a whole genome doubling in both cancerous and non-transformed p53 positive human cells. SNP array analysis and multicolor karyotyping revealed that induced whole-genome doubling led to variable aneuploidy. We found that chromosomal instability (CIN) is a frequent, but not a default outcome of whole genome doubling. The CIN phenotypes were accompanied by increased tolerance to mitotic errors that was mediated by suppression of the p53 signaling. Additionally, the expression of pro-apoptotic factors, such as iASPP and cIAP2, was downregulated. Furthermore, we found that whole genome doubling promotes resistance to a broad spectrum of chemotherapeutic drugs and stimulates anchorage-independent growth even in non-transformed p53-positive human cells. Taken together, whole genome doubling provides multifaceted benefits for malignant growth. Our findings provide new insight why genome-doubling promotes tumorigenesis and correlates with poor survival in cancer