Abstract
The cause of human cancers is imputed to the genetic alterations at nucleotide and chromosomal levels of ill-fated cells. It has long been recognized that genetic instability—the hallmark of human cancers—is responsible for the cellular changes that confer progressive transformation on cancerous cells. How cancer cells acquire genetic instability, however, is unclear. We propose that tumor development is a result of expansion and progression—two complementary aspects that collaborate with the tumor microenvironment—hypoxia in particular, on genetic alterations through the induction of genetic instability. In this article, we review the recent literature regarding how hypoxia functionally impairs various DNA repair pathways resulting in genetic instability and discuss the biomedical implications in cancer biology and treatment.
Similar content being viewed by others
Abbreviations
- DSB:
-
double-strand break
- HIF:
-
hypoxia-inducible factor
- HR:
-
homologous recombination
- HRE:
-
hypoxia-responsive element
- MMR:
-
mismatch repair
- NER:
-
nucleotide excision repair
- NHEJ:
-
nonhomologous end-joining
References
Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70
Vogelstein B, Kinzler KW (2004) Cancer genes and the pathways they control. Nat Med 10:789–799
Hahn WC, Weinberg RA (2002) Rules for making human tumor cells. N Engl J Med 347:1593–1603
Koshiji M, Huang LE (2004) Dynamic balancing of the dual nature of HIF-1alpha for cell survival. Cell Cycle 3:853–854
Harris AL (2002) Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer 2:38–47
Hockel M, Vaupel P (2001) Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst 93:266–276
Bindra RS, Glazer PM (2005) Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis. Mutat Res 569:75–85
Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514
Huang LE, Arany Z, Livingston DM, Bunn HF (1996) Activation of hypoxia-inducible transcription factor depends primarily upon redox-sensitive stabilization of its alpha subunit. J Biol Chem 271:32253–32259
Huang LE, Gu J, Schau M, Bunn HF (1998) Regulation of hypoxia-inducible factor 1alpha is mediated by an O2-dependent degradation domain via the ubiquitin-proteasome pathway. Proc Natl Acad Sci USA 95:7987–7992
Pugh CW, O’Rourke JF, Nagao M, Gleadle JM, Ratcliffe PJ (1997) Activation of hypoxia-inducible factor-1; definition of regulatory domains within the alpha subunit. J Biol Chem 272:11205–11214
Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275
Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol 2:423–427
Tanimoto K, Makino Y, Pereira T, Poellinger L (2000) Mechanism of regulation of the hypoxia-inducible factor-1alpha by the von Hippel-Lindau tumor suppressor protein. Embo J 19:4298–4309
Ivan M, Kondo K, Yang H, Kim W, Valiando J, Ohh M, Salic A, Asara JM, Lane WS, Kaelin WG Jr (2001) HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 292:464–468
Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292:468–472
Yu F, White SB, Zhao Q, Lee FS (2001) HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation. Proc Natl Acad Sci USA 98:9630–9635
Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O’Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ (2001) C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107:43–54
Bruick RK, McKnight SL (2001) A conserved family of prolyl-4-hydroxylases that modify HIF. Science 294:1337–1340
Berra E, Benizri E, Ginouves A, Volmat V, Roux D, Pouyssegur J (2003) HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. Embo J 22:4082–4090
Semenza GL (2002) HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med 8:S62–S67
Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM (1996) An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci USA 93:12969–12973
Semenza GL, Jiang BH, Leung SW, Passantino R, Concordet JP, Maire P, Giallongo A (1996) Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1. J Biol Chem 271:32529–32537
Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721–732
Koshiji M, Kageyama Y, Pete EA, Horikawa I, Barrett JC, Huang LE (2004) HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. Embo J 23:1949–1956
Mack FA, Patel JH, Biju MP, Haase VH, Simon MC (2005) Decreased growth of Vhl−/− fibrosarcomas is associated with elevated levels of cyclin kinase inhibitors p21 and p27. Mol Cell Biol 25:4565–4578
Li CY, Little JB, Hu K, Zhang W, Zhang L, Dewhirst MW, Huang Q (2001) Persistent genetic instability in cancer cells induced by non-DNA-damaging stress exposures. Cancer Res 61:428–432
Paquette B, Little JB (1994) In vivo enhancement of genomic instability in minisatellite sequences of mouse C3H/10T1/2 cells transformed in vitro by X-rays. Cancer Res 54:3173–3178
Reynolds TY, Rockwell S, Glazer PM (1996) Genetic instability induced by the tumor microenvironment. Cancer Research 56:5754–5757
Papp-Szabo E, Josephy PD, Coomber BL (2005) Microenvironmental influences on mutagenesis in mammary epithelial cells. Int J Cancer 116:679–685
Hammond EM, Green SL, Giaccia AJ (2003) Comparison of hypoxia-induced replication arrest with hydroxyurea and aphidicolin-induced arrest. Mutat Res 532:205–213
Yuan J, Glazer PM (1998) Mutagenesis induced by the tumor microenvironment. Mutat Res 400:439–446
Welbourn CR, Goldman G, Paterson IS, Valeri CR, Shepro D, Hechtman HB (1991) Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil. Br J Surg 78:651–655
Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362:709–715
Smith DI, Huang H, Wang L (1998) Common fragile sites and cancer (review). Int J Oncol 12:187–196
Rice GC, Spiro IJ, Ling CC (1985) Detection of S-phase overreplication following chronic hypoxia using a monoclonal anti-BrdUrd. Int J Radiat Oncol Biol Phys 11:1817–1822
Young SD, Marshall RS, Hill RP (1988) Hypoxia induces DNA overreplication and enhances metastatic potential of murine tumor cells. Proc Natl Acad Sci USA 85:9533–9537
Rice GC, Hoy C, Schimke RT (1986) Transient hypoxia enhances the frequency of dihydrofolate reductase gene amplification in Chinese hamster ovary cells. Proc Natl Acad Sci USA 83:5978–5982
Coquelle A, Toledo F, Stern S, Bieth A, Debatisse M (1998) A new role for hypoxia in tumor progression: induction of fragile site triggering genomic rearrangements and formation of complex DMs and HSRs. Mol Cell 2:259–265
Buttel I, Fechter A, Schwab M (2004) Common fragile sites and cancer: targeted cloning by insertional mutagenesis. Ann N Y Acad Sci 1028:14–27
Arlt MF, Casper AM, Glover TW (2003) Common fragile sites. Cytogenet Genome Res 100:92–100
Zhu Y, McAvoy S, Kuhn R, Smith DI (2006) RORA, a large common fragile site gene, is involved in cellular stress response. Oncogene 25:2901–2908
Buermeyer AB, Deschenes SM, Baker SM, Liskay RM (1999) Mammalian DNA mismatch repair. Annu Rev Genet 33:533–564
Mihaylova VT, Bindra RS, Yuan J, Campisi D, Narayanan L, Jensen R, Giordano F, Johnson RS, Rockwell S, Glazer PM (2003) Decreased expression of the DNA mismatch repair gene Mlh1 under hypoxic stress in mammalian cells. Mol Cell Biol 23:3265–3273
Koshiji M, To KK, Hammer S, Kumamoto K, Harris AL, Modrich P, Huang LE (2005) HIF-1alpha induces genetic instability by transcriptionally downregulating MutSalpha expression. Mol Cell 17:793–803
Shahrzad S, Quayle L, Stone C, Plumb C, Shirasawa S, Rak JW, Coomber BL (2005) Ischemia-induced K-ras mutations in human colorectal cancer cells: role of microenvironmental regulation of MSH2 expression. Cancer Res 65:8134–8141
To KK, Koshiji M, Hammer S, Huang LE (2005) Genetic instability: the dark side of the hypoxic response. Cell Cycle 4:881–882
Yuan J, Narayanan L, Rockwell S, Glazer PM (2000) Diminished DNA repair and elevated mutagenesis in mammalian cells exposed to hypoxia and low pH. Cancer Res 60:4372–4376
Bindra RS, Schaffer PJ, Meng A, Woo J, Maseide K, Roth ME, Lizardi P, Hedley DW, Bristow RG, Glazer PM (2004) Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells. Mol Cell Biol 24:8504–8518
Bindra RS, Gibson SL, Meng A, Westermark U, Jasin M, Pierce AJ, Bristow RG, Classon MK, Glazer PM (2005) Hypoxia-induced down-regulation of BRCA1 expression by E2Fs. Cancer Res 65:11597–11604
Luk CK, Veinot-Drebot L, Tjan E, Tannock IF (1990) Effect of transient hypoxia on sensitivity to doxorubicin in human and murine cell lines. J Natl Cancer Inst 82:684–692
Hammond EM, Denko NC, Dorie MJ, Abraham RT, Giaccia AJ (2002) Hypoxia links ATR and p53 through replication arrest. Mol Cell Biol 22:1834–1843
Hammond EM, Dorie MJ, Giaccia AJ (2003) ATR/ATM targets are phosphorylated by ATR in response to hypoxia and ATM in response to reoxygenation. J Biol Chem 278:12207–12213
Hammond EM, Dorie MJ, Giaccia AJ (2004) Inhibition of ATR leads to increased sensitivity to hypoxia/reoxygenation. Cancer Res 64:6556–6562
Nelson DA, Tan TT, Rabson AB, Anderson D, Degenhardt K, White E (2004) Hypoxia and defective apoptosis drive genomic instability and tumorigenesis. Genes Dev 18:2095–2107
Kim MS, Baek JH, Bae MK, Kim KW (2001) Human rad21 gene, hHR21(SP), is downregulated by hypoxia in human tumor cells. Biochem Biophys Res Commun 281:1106–1112
Meng AX, Jalali F, Cuddihy A, Chan N, Bindra RS, Glazer PM, Bristow RG (2005) Hypoxia down-regulates DNA double strand break repair gene expression in prostate cancer cells. Radiother Oncol 76:168–176
To KK, Sedelnikova OA, Samons M, Bonner WM, Huang LE (2006) The phosphorylation status of PAS-B distinguishes HIF-1alpha from HIF-2alpha in NBS1 repression. Embo J 25(20):4784–4794
Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd, Hays L, Morgan WF, Petrini JH (1998) The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 93:477–486
D’Amours D, Jackson SP (2002) The Mre11 complex: at the crossroads of DNA repair and checkpoint signalling. Nat Rev Mol Cell Biol 3:317–327
Huang LE, Bunn HF (2003) Hypoxia-inducible factor and its biomedical relevance. J Biol Chem 278:19575–19578
Bindra RS, Schaffer PJ, Meng A, Woo J, Maseide K, Roth ME, Lizardi P, Hedley DW, Bristow RG, Glazer PM (2005) Alterations in DNA repair gene expression under hypoxia: elucidating the mechanisms of hypoxia-induced genetic instability. Ann N Y Acad Sci 1059:184–195
Attwooll C, Denchi EL, Helin K (2004) The E2F family: specific functions and overlapping interests. Embo J 23:4709–4716
Dimova DK, Dyson NJ (2005) The E2F transcriptional network: old acquaintances with new faces. Oncogene 24:2810–2826
Cam H, Dynlacht BD (2003) Emerging roles for E2F: beyond the G1/S transition and DNA replication. Cancer Cell 3:311–316
Zhu W, Giangrande PH, Nevins JR (2004) E2Fs link the control of G1/S and G2/M transcription. Embo J 23:4615–4626
Helt AM, Galloway DA (2001) Destabilization of the retinoblastoma tumor suppressor by human papillomavirus type 16 E7 is not sufficient to overcome cell cycle arrest in human keratinocytes. J Virol 75:6737–6747
Um JH, Kang CD, Bae JH, Shin GG, Kim do W, Kim DW, Chung BS, Kim SH (2004) Association of DNA-dependent protein kinase with hypoxia inducible factor-1 and its implication in resistance to anticancer drugs in hypoxic tumor cells. Exp Mol Med 36:233–242
Venkitaraman AR (2002) Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell 108:171–182
Kinzler KW, Vogelstein B (1997) Cancer-susceptibility genes. Gatekeepers and caretakers. Nature 386:761–763
Zhang J, Willers H, Feng Z, Ghosh JC, Kim S, Weaver DT, Chung JH, Powell SN, Xia F (2004) Chk2 phosphorylation of BRCA1 regulates DNA double-strand break repair. Mol Cell Biol 24:708–718
Liu L, Cash TP, Jones RG, Keith B, Thompson CB, Simon MC (2006) Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell 21:521–531
Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185
Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3:187–197
Friedberg EC (2003) DNA damage and repair. Nature 421:436–440
Graeber TG, Osmanian C, Jacks T, Housman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature 379:88–91
Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9:677–684
Unruh A, Ressel A, Mohamed HG, Johnson RS, Nadrowitz R, Richter E, Katschinski DM, Wenger RH (2003) The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 22:3213–3220
Song X, Liu X, Chi W, Liu Y, Wei L, Wang X, Yu J (2006) Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-1alpha gene. Cancer Chemother Pharmacol
Moeller BJ, Cao Y, Li CY, Dewhirst MW (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5:429–441
Moeller BJ, Dreher MR, Rabbani ZN, Schroeder T, Cao Y, Li CY, Dewhirst MW (2005) Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8:99–110
Moeller BJ, Dewhirst MW (2006) HIF-1 and tumour radiosensitivity. Br J Cancer 95:15
Williams KJ, Telfer BA, Xenaki D, Sheridan MR, Desbaillets I, Peters HJ, Honess D, Harris AL, Dachs GU, van der Kogel A, Stratford IJ (2005) Enhanced response to radiotherapy in tumours deficient in the function of hypoxia-inducible factor-1. Radiother Oncol 75:89–98
Maynard MA, Evans AJ, Hosomi T, Hara S, Jewett MA, Ohh M (2005) Human HIF-3alpha4 is a dominant-negative regulator of HIF-1 and is down-regulated in renal cell carcinoma. FASEB J 19:1396–1406
Turner KJ, Moore JW, Jones A, Taylor CF, Cuthbert-Heavens D, Han C, Leek RD, Gatter KC, Maxwell PH, Ratcliffe PJ, Cranston D, Harris AL (2002) Expression of hypoxia-inducible factors in human renal cancer: relationship to angiogenesis and to the von Hippel-Lindau gene mutation. Cancer Res 62:2957–2961
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Huang, L.E., Bindra, R.S., Glazer, P.M. et al. Hypoxia-induced genetic instability—a calculated mechanism underlying tumor progression. J Mol Med 85, 139–148 (2007). https://doi.org/10.1007/s00109-006-0133-6
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-006-0133-6