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Hsp90 as a Capacitor of Both Genetic and Epigenetic Changes in the Genome During Cancer Progression and Evolution

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Stress-Induced Mutagenesis

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Abstract

In this chapter, we focus on the role of the chaperone protein Hsp90 as a capacitor for morphological variation that is released during times of stress. Hsp90 helps to fold numerous client proteins, which constitute a veritable “who’s who” of important signaling molecules, such as Akt, Raf, Src, chromatin-modifying proteins, nuclear hormone receptors, and kinetochore assembly proteins. We first review evidence that Hsp90 functions trans-generationally as a capacitor for morphological variation via both genetic and epigenetic means: in the former by revealing cryptic genetic variation and in the latter by generating heritable epialleles. Then we discuss two mechanisms by which altered Hsp90 function can mutate DNA: transposon mobilization, and chromosomal aneuploidy. Next, we hypothesize how beneficial cryptic epigenetic variation might be stabilized, or locked in place, by the directed DNA-level mutation of epigenetically assimilated epialleles. Finally, we describe how Hsp90 functions intra-generationally within an organism’s lifetime by releasing cryptic phenotypic variation during development in a stressful environment, and how this can be hijacked during the progression of diseases such as cancer.

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References

  • Bartel DP, Chen CZ (2004) Micromanagers of gene expression: the potentially widespread inf.uence of metazoan microRNAs. Nat Rev Genet 5(5):396–400

    Article  PubMed  CAS  Google Scholar 

  • Branham WS et al (1988) Uterine abnormalities in rats exposed neonatally to diethylstilbestrol, ethynylestradiol, or clomiphene citrate. Toxicology 51(2–3):201–212

    Article  PubMed  CAS  Google Scholar 

  • Brennecke J et al (2007) Discrete small RNA-generating loci as master regulators of transposon activity in Drosophila. Cell 128(6):1089–1103

    Article  PubMed  CAS  Google Scholar 

  • Brooks JL (1965) Predation and relative helmet size in cyclomorphic daphnia. Proc Natl Acad Sci USA 53(1):119–126

    Article  PubMed  CAS  Google Scholar 

  • Carroll SB (2005) Endless forms most beautiful: the new science of evo devo and the making of the animal kingdom, 1st edn. Norton, New York, p 350, xi

    Google Scholar 

  • Chang TC, Mendell JT (2007) microRNAs in vertebrate physiology and human disease. Annu Rev Genomics Hum Genet 8:215–239

    Article  PubMed  CAS  Google Scholar 

  • Chen G et al (2012) Hsp90 stress potentiates rapid cellular adaptation through induction of aneuploidy. Nature 482(7384):246–250

    PubMed  CAS  Google Scholar 

  • Chouard T (2010) Evolution: revenge of the hopeful monster. Nature 463(7283):864–867

    Article  PubMed  CAS  Google Scholar 

  • Cohen SM, Brennecke J (2006) Developmental biology. Mixed messages in early development. Science 312(5770):65–66

    Article  PubMed  CAS  Google Scholar 

  • Cohen SM, Brennecke J, Stark A (2006) Denoising feedback loops by thresholding—a new role for microRNAs. Genes Dev 20(20):2769–2772

    Article  PubMed  CAS  Google Scholar 

  • Cohen A et al (2007) Alterations in microRNA expression profiles reveal a novel pathway for estrogen regulation. Endocrinology 149(4):1687–1696

    Google Scholar 

  • Darwin C (1859) The origin of the species. Suriano G (ed) Random House

    Google Scholar 

  • Darwin C (1871) The descent of man, and selection in relation to sex. D. Appleton and company, New York

    Book  Google Scholar 

  • Darwin C (1883) Variation in animals and plants under domestication. Appleton and Co., New York

    Google Scholar 

  • David R (2012) DNA repair: how chromosomes find their “soul mate. Nat Rev Mol Cell Biol 13(5):281

    Google Scholar 

  • Dews M et al (2006) Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet 38(9):1060–1065

    Article  PubMed  CAS  Google Scholar 

  • Dezwaan DC, Freeman BC (2008) HSP90: the Rosetta stone for cellular protein dynamics? Cell Cycle 7(8):1006–1012

    Article  PubMed  CAS  Google Scholar 

  • Fondon JW, Garner HR (2004) Molecular origins of rapid and continuous morphological evolution. Proc Natl Acad Sci USA 101(52):18058–18063

    Article  PubMed  CAS  Google Scholar 

  • Gangaraju VK et al (2011) Drosophila Piwi functions in Hsp90-mediated suppression of phenotypic variation. Nat Genet 43(2):153–158

    Article  PubMed  CAS  Google Scholar 

  • Garfinkel MD et al (2004) Multigenerational selection and detection of altered histone acetylation and methylation patterns: toward a quantitative epigenetics in Drosophila. Methods Mol Biol 287:151–168

    PubMed  CAS  Google Scholar 

  • Gilloteaux J, Steggles AW (1985) Endometrium cell surface abnormalities in the Syrian hamster as a result of in utero exposure to diethylstilbestrol. Scan Electron Microsc (Pt 1):303–309.

    Google Scholar 

  • Gould SJ (1980) The panda’s thumb: more reflections in natural history, 1st edn. Norton, New York, 343

    Google Scholar 

  • Griffiths-Jones S (2006) miRBase: the microRNA sequence database. Methods Mol Biol 342:129–138

    PubMed  CAS  Google Scholar 

  • Griffiths-Jones S et al (2006) miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 34(Database Issue):D140–D144

    Article  PubMed  CAS  Google Scholar 

  • Grimaud C et al (2006) RNAi components are required for nuclear clustering of Polycomb group response elements. Cell 124(5):957–971

    Article  PubMed  CAS  Google Scholar 

  • Grimson A et al (2007) MicroRNA targeting specificity in mammals: determinants beyond seed pairing. Mol Cell 27(1):91–105

    Article  PubMed  CAS  Google Scholar 

  • Hallson G et al (2008) The Drosophila cohesin subunit Rad21 is a trithorax group (trxG) protein. Proc Natl Acad Sci USA 105(34):12405–12410

    Article  PubMed  CAS  Google Scholar 

  • Hamamoto R et al (2004) SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol 6(8):731–740

    Article  PubMed  CAS  Google Scholar 

  • Hatch EE et al (2001) Incidence of squamous neoplasia of the cervix and vagina in women exposed prenatally to diethylstilbestrol (United States). Canc Causes Contr 12(9):837–845

    Article  CAS  Google Scholar 

  • Holeski LM (2007) Within and between generation phenotypic plasticity in trichome density of Mimulus guttatus. J Evol Biol 20(6):2092–2100

    Article  PubMed  CAS  Google Scholar 

  • Huxley J (1942) Evolution, the modern synthesis. G. Allen & Unwin Ltd., London, p 645

    Google Scholar 

  • Iguchi T, Takasugi N (1987) Postnatal development of uterine abnormalities in mice exposed to DES in utero. Biol Neonate 52(2):97–103

    Article  PubMed  CAS  Google Scholar 

  • Jablonka E, Lamb MJ (2005) Evolution in four dimensions: genetic, epigenetic, behavioral, and symbolic variation in the history of life and mind. MIT Press, Cambridge, MA, p 462, x

    Google Scholar 

  • Jones-Rhoades MW, Bartel DP, Bartel B (2006) MicroRNAS and their regulatory roles in plants. Annu Rev Plant Biol 57:19–53

    Article  PubMed  CAS  Google Scholar 

  • Kent OA, Mendell JT (2006) A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes. Oncogene 25(46):6188–6196

    Article  PubMed  CAS  Google Scholar 

  • Knight WA 3rd et al (1980) Steroid hormone receptors in the management of human breast cancer. Ann Clin Res 12(5):202–207

    PubMed  Google Scholar 

  • Kohler HR et al (2009) Snail phenotypic variation and stress proteins: do different heat response strategies contribute to Waddington's widget in field populations? J Exp Zool Part B Mol Dev Evol 312(2):136–147

    Google Scholar 

  • Laforsch C, Tollrian R (2004) Embryological aspects of inducible morphological defenses in Daphnia. J Morphol 262(3):701–707

    Article  PubMed  Google Scholar 

  • Lamarck JBP (1809) Zoological philosophy. Chicago Press, Chicago

    Google Scholar 

  • Leavitt WW, Evans RW, Hendry WJ 3rd (1981) Etiology of DES-induced uterine tumors in the Syrian hamster. Adv Exp Med Biol 138:63–86

    Article  PubMed  CAS  Google Scholar 

  • Li S et al (2001) Promoter CpG methylation of Hox-a10 and Hox-a11 in mouse uterus not altered upon neonatal diethylstilbestrol exposure. Mol Carcinog 32(4):213–219

    Article  PubMed  CAS  Google Scholar 

  • Li S et al (2003a) Environmental exposure, DNA methylation, and gene regulation: lessons from diethylstilbesterol-induced cancers. Ann N Y Acad Sci 983:161–169

    Article  PubMed  CAS  Google Scholar 

  • Li S et al (2003b) Neonatal diethylstilbestrol exposure induces persistent elevation of c-fos expression and hypomethylation in its exon-4 in mouse uterus. Mol Carcinog 38(2):78–84

    Article  PubMed  CAS  Google Scholar 

  • Lu X et al (2011) Hsp90 inhibitors and drug resistance in cancer: the potential benefits of combination therapies of Hsp90 inhibitors and other anti-cancer drugs. Biochem Pharmacol 83(8):995–1004

    Google Scholar 

  • Matranga C, Zamore PD (2007) Small silencing RNAs. Curr Biol 17(18):R789–R793

    Article  PubMed  CAS  Google Scholar 

  • Matyash A, Chung HR, Jackle H (2004) Genome-wide mapping of in vivo targets of the Drosophila transcription factor Kruppel. J Biol Chem 279(29):30689–30696

    Article  PubMed  CAS  Google Scholar 

  • McClintock B (1984) The significance of responses of the genome to challenge. Science 226(4676):792–801

    Article  PubMed  CAS  Google Scholar 

  • McLachlan JA, Newbold RR, Bullock BC (1980) Long-term effects on the female mouse genital tract associated with prenatal exposure to diethylstilbestrol. Cancer Res 40(11):3988–3999

    PubMed  CAS  Google Scholar 

  • McLaren A (1999) Too late for the midwife toad: stress, variability and Hsp90. Trends Genet TIG 15(5):169–171

    Article  CAS  Google Scholar 

  • Medlock KL, Branham WS, Sheehan DM (1992) Long-term effects of postnatal exposure to diethylstilbestrol on uterine estrogen receptor and growth. J Steroid Biochem Mol Biol 42(1):23–28

    Article  PubMed  CAS  Google Scholar 

  • Meiklejohn CD, Hartl DL (2002) A single mode of canalization. Trends Ecol Evol 17(10):468–473

    Article  Google Scholar 

  • Mendel G (1865) Experiments in plant hybridisation. Harvard University Press, Boston

    Google Scholar 

  • Moxon R, Bayliss C, Hood D (2006) Bacterial contingency loci: the role of simple sequence DNA repeats in bacterial adaptation. Annu Rev Genet 40:307–333

    Article  PubMed  CAS  Google Scholar 

  • Newbold RR, Bullock BC, McLachlan JA (1990) Uterine adenocarcinoma in mice following developmental treatment with estrogens: a model for hormonal carcinogenesis. Cancer Res 50(23):7677–7681

    PubMed  CAS  Google Scholar 

  • Newbold RR et al (1998) Increased tumors but uncompromised fertility in the female descendants of mice exposed developmentally to diethylstilbestrol. Carcinogenesis 19(9):1655–1663

    Article  PubMed  CAS  Google Scholar 

  • Newbold RR et al (2000) Proliferative lesions and reproductive tract tumors in male descendants of mice exposed developmentally to diethylstilbestrol. Carcinogenesis 21(7):1355–1363

    Article  PubMed  CAS  Google Scholar 

  • O’Donnell KA et al (2005) c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435(7043):839–843

    Article  PubMed  Google Scholar 

  • Oda S et al (2011) Morphological changes in Daphnia galeata induced by a crustacean terpenoid hormone and its analog. Environ Toxicol Chem/SETAC 30(1):232–238

    Article  CAS  Google Scholar 

  • Phalke S et al (2009) Retrotransposon silencing and telomere integrity in somatic cells of Drosophila depends on the cytosine-5 methyltransferase DNMT2. Nat Genet 41(6):696–702

    Article  PubMed  CAS  Google Scholar 

  • Pigliucci M (2003) Epigenetics is back! Hsp90 and phenotypic variation. Cell Cycle 2(1):34–35

    Article  PubMed  CAS  Google Scholar 

  • Pigliucci M, Müller G, Konrad Lorenz Institute for Evolution and Cognition Research (2010) Evolution, the extended synthesis. MIT Press, Cambridge, MA, p 495, viii

    Google Scholar 

  • Queitsch C, Sangster TA, Lindquist S (2002) Hsp90 as a capacitor of phenotypic variation. Nature 417(6889):618–624

    Article  PubMed  CAS  Google Scholar 

  • Rakyan V, Whitelaw E (2003) Transgenerational epigenetic inheritance. Curr Biol 13(1):R6

    Article  PubMed  CAS  Google Scholar 

  • Rehwinkel J et al (2006) Genome-wide analysis of mRNAs regulated by Drosha and Argonaute proteins in Drosophila melanogaster. Mol Cell Biol 26(8):2965–2975

    Article  PubMed  CAS  Google Scholar 

  • Roux F et al (2011) Genome-wide epigenetic perturbation jump-starts patterns of heritable variation found in nature. Genetics 188(4):1015–1017

    Article  PubMed  CAS  Google Scholar 

  • Ruden DM (2011) The (new) new synthesis and epigenetic capacitors of morphological evolution. Nat Genet 43(2):88–89

    Article  PubMed  CAS  Google Scholar 

  • Ruden DM, Lu X (2008) Hsp90 affecting chromatin remodeling might explain transgenerational epigenetic inheritance in Drosophila. Curr Genom 9(7):500–508

    Article  CAS  Google Scholar 

  • Ruden DM et al (2003) Waddington’s widget: Hsp90 and the inheritance of acquired characters. Semin Cell Dev Biol 14(5):301–310

    Article  PubMed  CAS  Google Scholar 

  • Ruden DM et al (2005a) Hsp90 and environmental impacts on epigenetic states: a model for the trans-generational effects of diethylstibesterol on uterine development and cancer. Human Mol Genet 14(1):R149–R155

    Article  CAS  Google Scholar 

  • Ruden DM et al (2005b) Epigenetic regulation of trinucleotide repeat expansions and contractions and the “biased embryos” hypothesis for rapid morphological evolution. Curr Genom 6(3):145–155

    Article  CAS  Google Scholar 

  • Ruden DM et al (2008) The EDGE hypothesis: epigenetically directed genetic errors in repeat-­containing proteins (RCPs) involved in evolution, neuroendocrine signaling, and cancer. Front Neuroendocrinol 29(3):428–444

    Article  PubMed  CAS  Google Scholar 

  • Rutherford SL, Lindquist S (1998) Hsp90 as a capacitor for morphological evolution. Nature 396(6709):336–342

    Article  PubMed  CAS  Google Scholar 

  • Rutherford S, Hirate Y, Swalla BJ (2007) The Hsp90 capacitor, developmental remodeling, and evolution: the robustness of gene networks and the curious evolvability of metamorphosis. Crit Rev Biochem Mol Biol 42(5):355–372

    Article  PubMed  CAS  Google Scholar 

  • Sandmann T, Cohen SM (2007) Identification of Novel Drosophila melanogaster MicroRNAs. PLoS One 2(11):e1265

    Article  PubMed  Google Scholar 

  • Saurin AJ et al (1998) The human polycomb group complex associates with pericentromeric heterochromatin to form a novel nuclear domain. J Cell Biol 142(4):887–898

    Article  PubMed  CAS  Google Scholar 

  • Schaefer M, Lyko F (2010) Lack of evidence for DNA methylation of Invader4 retroelements in Drosophila and implications for Dnmt2-mediated epigenetic regulation. Nat Genet 42(11):920–921, author reply 921

    Article  PubMed  CAS  Google Scholar 

  • Scoville AG et al (2011) Differential regulation of a MYB transcription factor is correlated with transgenerational epigenetic inheritance of trichome density in Mimulus guttatus. New Phytol 191(1):251–263

    Article  PubMed  CAS  Google Scholar 

  • Sollars V et al (2003) Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nat Genet 33(1):70–74

    Article  PubMed  CAS  Google Scholar 

  • Specchia V et al (2010) Hsp90 prevents phenotypic variation by suppressing the mutagenic activity of transposons. Nature 463(7281):662–665

    Article  PubMed  CAS  Google Scholar 

  • Stark A et al (2008) A single Hox locus in Drosophila produces functional microRNAs from opposite DNA strands. Genes Dev 22(1):8–13

    Article  PubMed  CAS  Google Scholar 

  • Stedman W et al (2008) Cohesins localize with CTCF at the KSHV latency control region and at cellular c-myc and H19/Igf2 insulators. EMBO J 27(4):654–666

    Article  PubMed  CAS  Google Scholar 

  • Taipale M, Jarosz DF, Lindquist S (2010) HSP90 at the hub of protein homeostasis: emerging mechanistic insights. Nature reviews. Mol Cell Biol 11(7):515–528

    CAS  Google Scholar 

  • Tariq M et al (2009) Trithorax requires Hsp90 for maintenance of active chromatin at sites of gene expression. Proc Nat Acad Sci USA 106(4):1157–1162

    Article  CAS  Google Scholar 

  • Tolkien JRR (1954) The lord of the rings. Allen & Unwin, London

    Google Scholar 

  • Trepel J et al (2010) Targeting the dynamic HSP90 complex in cancer. Nat Rev Cancer 10(8):537–549

    Article  PubMed  CAS  Google Scholar 

  • Turusov VS et al (1992) Occurrence of tumours in the descendants of CBA male mice prenatally treated with diethylstilbestrol. Int J Cancer 50(1):131–135

    Article  PubMed  CAS  Google Scholar 

  • Waddington CH (1942) Canalization of development and the inheritance of acquired characters. Nature 150:563–565

    Article  Google Scholar 

  • Waddington CH (1953) Genetic assimilation of an acquired character. Evolution 7:118–126

    Article  Google Scholar 

  • Waddington CH (1956) Genetic assimilation of the bithorax complex. Evolution 10:1–13

    Article  Google Scholar 

  • Waddington CH (1974) A catastrophe theory of evolution. Ann NY Acad Sci 231(1):32–42

    Article  PubMed  CAS  Google Scholar 

  • Walker BE, Haven MI (1997) Intensity of multigenerational carcinogenesis from diethylstilbestrol in mice. Carcinogenesis 18(4):791–793

    Article  PubMed  CAS  Google Scholar 

  • Wang Y et al (2006) Functional CpG methylation system in a social insect. Science 314(5799):645–647

    Article  PubMed  CAS  Google Scholar 

  • Whitesell L, Lindquist SL (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5(10):761–772

    Article  PubMed  CAS  Google Scholar 

  • Zambon RA, Vakharia VN, Wu LP (2006) RNAi is an antiviral immune response against a dsRNA virus in Drosophila melanogaster. Cell Microbiol 8(5):880–889

    Article  PubMed  CAS  Google Scholar 

  • Zamore PD (2007) RNA silencing: genomic defence with a slice of pi. Nature 446(7138):864–865

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments 

This work was supported by NIH grants ES012933 and ES02183 to D.M.R., and DK071073 to X.L.

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Authors and Affiliations

  1. Institute of Environmental Health Sciences, Wayne State University, Detroit, MI, 48201, USA

    Xiangyi Lu, Luan Wang & Douglas M. Ruden

  2. Department of Obstetrics and Gynecology, C. S. Mott Center for Human Growth and Development, Wayne State University, Detroit, MI, 48201, USA

    Luan Wang & Douglas M. Ruden

  3. Department of Biochemistry and Microbiology, Joan C. Edwards School of Medicine, Marshall University, One John Marshall Drive, Huntington, WV, 25755, USA

    Vincent E. Sollars

  4. Department of Biological Sciences, University of Alabama in Huntsville, Huntsville, AL, 35899, USA

    Mark D. Garfinkel

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  1. Xiangyi Lu
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  2. Luan Wang
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  4. Mark D. Garfinkel
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Correspondence to Douglas M. Ruden .

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  1. , Department of Biological Sciences, Virginia Tech, 4100 Derring Lab, Blacksburg, 24061, Virginia, USA

    David Mittelman

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Lu, X., Wang, L., Sollars, V.E., Garfinkel, M.D., Ruden, D.M. (2013). Hsp90 as a Capacitor of Both Genetic and Epigenetic Changes in the Genome During Cancer Progression and Evolution. In: Mittelman, D. (eds) Stress-Induced Mutagenesis. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6280-4_5

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