Although nearly ubiquitous in cancer, aneuploidy exerts detrimental effects on human cells. We recently demonstrated that aneuploid human cells exhibit impaired heat shock factor protein 1 (HSF1) and HSP90 function, suggesting a functional link between two recurring features of cancer cells: aneuploidy and proteotoxic stress. Further, our fi ndings implicate HSF1 as a key factor in mitigating the effects of aneuploid

Donnelly, N.

Storchova, Z.

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Neysan Donnelly

Zuzana Storchová

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Molecular & Cellular Oncology

Aneuploidy and proteotoxic stress in cancer

MPG.PuRe

Full Terms & Conditions of access and use can be found athttp://www.tandfonline.com/action/journalInformation?journalCode=kmco20Download by: [Library of MPI Biochemistry & MPI Neurobiology] Date: 17 February 2016, At: 05:38Molecular & Cellular OncologyISSN: (Print) 2372-3556 (Online) Journal homepage: http://www.tandfonline.com/loi/kmco20Aneuploidy and proteotoxic stress in cancerNeysan Donnelly & Zuzana StorchováTo cite this article: Neysan Donnelly & Zuzana Storchová (2015) Aneuploidy andproteotoxic stress in cancer, Molecular & Cellular Oncology, 2:2, e976491, DOI:10.4161/23723556.2014.976491To link to this article:  http://dx.doi.org/10.4161/23723556.2014.976491© 2015 The Author(s). Published withlicense by Taylor & Francis Group, LLC©Neysan Donnelly and Zuzana StorchováPublished online: 25 Feb 2015.Submit your article to this journal Article views: 192View related articles View Crossmark dataAneuploidy and proteotoxic stress in cancerNeysan Donnelly1 and Zuzana Storchova1,2,*1Group Maintenance of Genome Stability; Max Planck Institute of Biochemistry; Martinsried, Germany; 2Center for Integrated Protein Science;Ludwig-Maximilian-University; Munich, GermanyKeywords: aneuploidy, cancer, HSF1, HSP90, proteotoxic stressAlthough nearly ubiquitous in cancer, aneuploidy exerts detrimental effects on human cells. We recentlydemonstrated that aneuploid human cells exhibit impaired heat shock factor protein 1 (HSF1) and HSP90 function,suggesting a functional link between two recurring features of cancer cells: aneuploidy and proteotoxic stress. Further,our ﬁndings implicate HSF1 as a key factor in mitigating the effects of aneuploidy.Although the spectrum of mutationsand alterations in cancer cells is extremelycomplex, all cancers exhibit commoncharacteristics or hallmarks, as first pro-posed by Hanahan and Weinberg.1 In apaper published in 2009, Elledge and col-leagues made a compelling case that, inaddition to the classic hallmarks of cancer,diverse forms of cellular stress such as pro-teotoxic stress and high levels of DNAdamage represent unifying characteristicsof established malignant cells.2 This novelparadigm for understanding tumorigene-sis and cancer treatment posits that thestress phenotypes of tumors lead to theaddiction of cancer cells to pathways andmolecules that ameliorate cell stress. How-ever, how these stress phenotypes arise incancer is not yet fully understood.Proteotoxic stress and constitutiveactivation of the heat shock factor pro-tein 1 (HSF1)-regulated heat shockresponse (HSR) pathway are among therecurring features of malignant cells,and inhibition of molecular chaperonesrepresents a promising therapeutic strat-egy for cancer treatment.3 It has beenproposed that the heavy reliance of can-cer cells on protein-folding factorsstems from the role of chaperones inmitigating the stress associated withtumor development and from the largenumber of chaperones required to stabi-lize critical mutated oncogenes,although there may be additionalexplanations for these characteristics ofcancer cells.Aneuploidy, or an imbalanced karyo-type, is nearly ubiquitous among cancercells and has previously been proposedto be responsible for the proteotoxicstress of tumors.2 Analysis of modelyeast aneuploids has provided compel-ling evidence that aneuploidy elicits pro-teotoxic stress and impairs cellularprotein folding.4 However, until recentlyit has been difficult to directly study theeffects of aneuploidy in metazoans andthus mechanistic evidence supportingthis hypothesis in human cells has beenlacking. We previously established andcharacterized model human aneuploidcells that differ from their cognate dip-loids only by the presence of additionalchromosomes.5 Using luciferase-basedprotein folding sensors that are exqui-sitely sensitive to cellular protein foldingcapacity in general, and to heat shockprotein 90 (HSP90) function in particu-lar, we observed striking impairments inthese model aneuploids compared todiploid controls that were independentof the cell line and the extra chromo-some(s) introduced6 (Fig. 1). Consistentwith a defect in HSP90, aneuploidhuman cells were significantly more sen-sitive to HSP90 inhibition than cognatediploids. Treatment of aneuploid cellswith inhibitors of other protein foldingfactors or inducers of protein misfoldingdid not reveal any general sensitivity,indicating that the protein folding defectcaused by aneuploidy may indeed bespecific for HSP90.Analysis of the transcriptome and pro-teome showed consistent downregulationof HSP90 in a panel of aneuploid cellsand a more variable reduction in the levelsof other molecular chaperones. Thisprompted us to test whether the levels andactivity of HSF1, the master regulator ofinducible chaperone expression, were alsoaffected by aneuploidy. Strikingly, weobserved consistently lower protein, butnot mRNA, levels of HSF1 in aneuploidcells as well as a profound defect in theability to trigger the HSF1-dependentHSR (Fig. 1).Is the defective HSF1 function in aneu-ploid cells responsible for their impairedHSP90 activity? To address this question,we constructed cells carrying a third copyof chromosome 8, which carries the HSF1gene. We reasoned that the resulting cells,which are aneuploid and have increasedexpression of HSF1, might be protectedagainst the defect in protein foldingengendered by aneuploidy. Indeed, thesecells displayed no reduction in HSP90expression and no apparent defect inHSP90 function as measured using fold-ing sensors and resistance to HSP90© Neysan Donnelly and Zuzana Storchova*Correspondence to: Zuzana Storchova; E-mail: storchov@biochem.mpg.deSubmitted: 10/08/2014; Revised: 10/09/2014; Accepted: 10/09/2014http://dx.doi.org/10.4161/23723556.2014.976491This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Themoral rights of the named author(s) have been asserted.www.tandfonline.com e976491-1Molecular & Cellular OncologyMolecular & Cellular Oncology 2:2, e976491; April/May/June 2015; Published with license by Taylor & FrancisAUTHOR'S VIEWDownloaded by [Library of MPI Biochemistry & MPI Neurobiology] at 05:38 17 February 2016 inhibition. However, one cell line behavedmarkedly differently; in this clone, whichhad lost the extra copy of HSF1, weobserved reduced HSP90 expression andsensitivity to HSP90 inhibition. In furthersupport of a role for HSF1, exogenousoverexpression of a constitutively activeHSF1 protein rescued the protein-foldingdefect of aneuploid cells and improvedsurvival in the presence of a HSP90 inhib-itor (Fig. 1).Human aneuploid cells exhibit pro-found genome-wide alterations in bothprotein and mRNA expression5,7,8Intriguingly, the mechanisms underlyingthese phenomena are not understood. Weobserved a striking similarity between thetranscriptional response to HSF1 knock-down and the transcriptome changes ofaneuploid cells. Moreover, the levels ofprotein clients that strongly interact withHSP90 were lower in aneuploids com-pared to diploids. Further, we discovereda significant overlap between pathwaystargeted by HSP90 inhibition and thosethat are downregulated in aneuploid cells.Taken together, these findings suggestthat the altered gene expression observedin aneuploid cells is partly determined byimpaired protein folding capacity (Fig. 1).These findings may have two impor-tant implications for understandingtumorigenesis. First, by directly linkinganeuploidy with impaired protein foldingour observations lend strong support tothe idea that the proteotoxic stress experi-enced by tumor cells is at least partly dueto aneuploidy. Second, our experimentssuggest that the critical requirement forHSF1 in malignant transformation stemspartially from its role in protecting againstthe adverse effects of aneuploidy on pro-tein folding.Aneuploidy has also been associatedwith additional stress phenotypes of can-cer cells such as metabolic and oxidativestress.9 Based on these observations, weanticipate that future research may placeaneuploidy at the heart of the stress phe-notypes of cancer cells. Further, ourresults suggest that impaired protein fold-ing and its consequences may represent akey pathological feature of diseases such astrisomy syndromes.Disclosure of Potential Conflicts of InterestNo potential conflicts of interest weredisclosed.FundingThis work was supported by the MaxPlanck Society, the Center for IntegratedProtein Science, Munich and by a grantfrom Deutsche Forschungsgemeinschaftto Z.S.References1. Hanahan D, Weinberg RA. The hallmarks of cancer.Cell 2000; 100:57-70; PMID:106479312. Luo J, Solimini NL, Elledge SJ. Principles of cancer ther-apy: oncogene and non-oncogene addiction. Cell 2009;136:823-37; PMID:19269363; http://dx.doi.org/10.1016/j.cell.2009.02.0243. Whitesell L, Lindquist SL. HSP90 and the chaperoningof cancer. Nat Rev Cancer 2005; 5:761-72;PMID:161751774. Oromendia AB, Dodgson SE, Amon A. Aneuploidycauses proteotoxic stress in yeast. Genes Dev 2012;26:2696-708; PMID:23222101; http://dx.doi.org/10.1101/gad.207407.1125. Stingele S, Stoehr G, Peplowska K, Cox J, Mann M,Storchova Z. Global analysis of genome, transcrip-tome and proteome reveals the response to aneu-ploidy in human cells. Mol Syst Biol 2012; 8:608;PMID:22968442; http://dx.doi.org/10.1038/msb.2012.406. Donnelly N, Passerini V, DurrbaumM, Stingele S, Storch-ova Z. HSF1 deficiency and impaired HSP90-dependentprotein folding are hallmarks of aneuploid human cells.EMBO J 2014; 33:2374-87; PMID:25205676; http://dx.doi.org/10.15252/embj.2014886487. Durrbaum M, Kuznetsova AY, Passerini V, Stingele S,Stoehr G, Storchova Z. Unique features of the transcrip-tional response to model aneuploidy in human cells.BMC Genomics 2014; 15:139; PMID:24548329;http://dx.doi.org/10.1186/1471-2164-15-1398. Sheltzer JM, Torres EM, Dunham MJ, Amon A. Tran-scriptional consequences of aneuploidy. Proc Nat AcadSci U S A 2012; 109:12644-9; PMID:22802626; http://dx.doi.org/10.1073/pnas.12092271099. Pfau SJ, Amon A. Chromosomal instability and aneu-ploidy in cancer: from yeast to man. EMBO Rep 2012;13:515-27; PMID:22614003; http://dx.doi.org/10.1038/embor.2012.65Figure 1. The effects of aneuploidy on protein folding. Aneuploidy impairs the activity of heatshock factor 1 (HSF1) by an as yet undeﬁned mechanism. The reduced function of HSF1 partlydetermines the transcriptional changes in aneuploid cells and leads to lower expression and activityof HSP90. This in turn leads to lower expression and activity of HSP90-dependent proteins andpathways and sensitivity to HSP90 inhibitors. These effects can be suppressed by increased HSF1activity.e976491-2 Volume 2 Issue 2Molecular & Cellular OncologyDownloaded by [Library of MPI Biochemistry & MPI Neurobiology] at 05:38 17 February 2016 

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Aneuploidy and proteotoxic stress in cancer

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