The HPV E6/E7 Oncogenes: Key Factors for Viral Carcinogenesis and Therapeutic Targets

Trends in Microbiology

Volumn 26, Issue 2, 2018, Pages 158-168

  Hoppe Seyler, Karin ^a   Bossler, Felicitas ^a   Braun, Julia A ^a   Herrmann, Anja L ^a   Hoppe Seyler, Felix ^a  

^a GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

Author keywords

human papillomavirus; hypoxia; metabolism; mTOR; senescence; therapy

Indexed keywords

CANCER CELL; CELL AGING; CELL HYPOXIA; GENE TARGETING; HUMAN; NONHUMAN; ONCOGENE; ONCOGENE E6; ONCOGENE E7; PRIORITY JOURNAL; REVIEW; TUMOR VOLUME; VIRUS CARCINOGENESIS; WART VIRUS; CARCINOGENESIS; GENE EXPRESSION REGULATION; GENETICS; HOST PATHOGEN INTERACTION; HYPOXIA; METABOLISM; NEOPLASM; PAPILLOMAVIRIDAE; PATHOGENICITY; PHYSIOLOGY; VIROLOGY;

E6 PROTEIN, HUMAN PAPILLOMAVIRUS TYPE 16; MTOR PROTEIN, HUMAN; ONCOPROTEIN; PROTEIN E7; REPRESSOR PROTEIN; TARGET OF RAPAMYCIN KINASE;

CARCINOGENESIS; GENE EXPRESSION REGULATION, NEOPLASTIC; GENE EXPRESSION REGULATION, VIRAL; HOST-PATHOGEN INTERACTIONS; HUMANS; HYPOXIA; NEOPLASMS; ONCOGENE PROTEINS; ONCOGENE PROTEINS, VIRAL; PAPILLOMAVIRIDAE; PAPILLOMAVIRUS E7 PROTEINS; REPRESSOR PROTEINS; TOR SERINE-THREONINE KINASES;

EID: 85027519832     PISSN: 0966842X     EISSN: 18784380     Source Type: Journal    
DOI: 10.1016/j.tim.2017.07.007     Document Type: Review

References (106)

1. de Martel, C., et al. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int. J. Cancer 141 (2017), 664–670.
2. Bouvard, V., et al. A review of human carcinogens – part B: biological agents. Lancet Oncol. 10 (2009), 321–322.
3. Stein, A.P., et al. Prevalence of human papillomavirus in oropharyngeal cancer: a systematic review. Cancer J. 21 (2015), 138–146.
4. Berman, T.A., Schiller, J.T., Human papillomavirus in cervical cancer and oropharyngeal cancer: one cause, two diseases. Cancer 123 (2017), 2219–2229.
5. Schiller, J.T., Müller, M., Next generation prophylactic human papillomavirus vaccines. Lancet Oncol. 16 (2015), e217–e225.
6. Bruni, L., et al. Global estimates of human papillomavirus vaccination coverage by region and income level: a pooled analysis. Lancet Glob. Health 4 (2016), e453–e463.
7. zur Hausen, H., Disrupted dichotomous intracellular control of human papillomavirus infection in cancer of the cervix. Lancet 343 (1994), 955–957.
8. Schiffman, M., et al. Carcinogenic human papillomavirus infection. Nat. Rev. Dis. Primers, 2, 2016, 16086.
9. Dürst, M., et al. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc. Natl. Acad. Sci. U. S. A. 80 (1983), 3812–3815.
10. Schwarz, E., et al. Structure and transcription of human papillomavirus sequences in cervical carcinoma cells. Nature 314 (1985), 111–114.
11. Roman, A., Munger, K., The papillomavirus E7 proteins. Virology 445 (2013), 138–168.
12. Vande Pol, S.B., Klingelhutz, A.J., Papillomavirus E6 oncoproteins. Virology 445 (2013), 115–137.
13. Yamato, K., et al. New highly potent and specific E6 and E7 siRNAs for treatment of HPV16 positive cervical cancer. Cancer Gene Ther. 15 (2008), 140–153.
14. Jabbar, S.F., et al. Persistence of high-grade cervical dysplasia and cervical cancer requires the continuous expression of the human papillomavirus type 16 E7 oncogene. Cancer Res. 69 (2009), 4407–4414.
15. Hanahan, D., Weinberg, R.A., Hallmarks of cancer: the next generation. Cell 144 (2011), 646–674.
16. Mesri, E.A., et al. Human viral oncogenesis: a cancer hallmarks analysis. Cell Host Microbe 15 (2014), 266–282.
17. Neveu, G., et al. Comparative analysis of virus–host interactomes with a mammalian high-throughput protein complementation assay based on Gaussia princeps luciferase. Methods 58 (2012), 349–359.
18. White, E.A., et al. Comprehensive analysis of host cellular interactions with human papillomavirus E6 proteins identifies new E6 binding partners and reflects viral diversity. J. Virol. 86 (2012), 13174–13186.
19. White, E.A., et al. Systematic identification of interactions between host cell proteins and E7 oncoproteins from diverse human papillomaviruses. Proc. Natl. Acad. Sci. U. S. A. 109 (2012), E260–E267.
20. Martinez-Zapien, D., et al. Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53. Nature 529 (2016), 541–545.
21. Scheffner, M., et al. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63 (1990), 1129–1136.
22. Hawley-Nelson, P., et al. HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J. 8 (1989), 3905–3910.
23. Munger, K., et al. The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. Virology 63 (1989), 4417–4421.
24. Evan, G.I., Vousden, K.H., Proliferation, cell cycle and apoptosis in cancer. Nature 411 (2001), 342–348.
25. Jones, D.L., et al. Destabilization of the RB tumor suppressor protein and stabilization of p53 contribute to HPV type 16 E7-induced apoptosis. Virology 239 (1997), 97–107.
26. DeFilippis, R.A., et al. Endogenous human papillomavirus E6 and E7 proteins differentially regulate proliferation, senescence, and apoptosis in HeLa cervical carcinoma cells. J. Virol. 77 (2003), 1551–1563.
27. Butz, K., et al. Induction of apoptosis in human papillomaviruspositive cancer cells by peptide aptamers targeting the viral E6 oncoprotein. Proc. Natl. Acad. Sci. U. S. A. 97 (2000), 6693–6697.
28. Butz, K., et al. siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells. Oncogene 22 (2003), 5938–5945.
29. Klingelhutz, A.J., et al. Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature 380 (1996), 79–82.
30. Ganti, K., et al. The human papillomavirus E6 PDZ binding motif: from life cycle to malignancy. Viruses 7 (2015), 3530–3551.
31. Lee, S.S., et al. Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein. Proc. Natl. Acad. Sci. U. S. A. 94 (1997), 6670–6675.
32. Nakagawa, S., Huibregtse, J.M., Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase. Mol. Cell. Biol. 20 (2000), 8244–8253.
33. Glaunsinger, B.A., et al. Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins. Oncogene 19 (2000), 5270–5280.
34. Ganti, K., et al. Interaction of the human papillomavirus E6 oncoprotein with sorting nexin 27 modulates endocytic cargo transport pathways. PLoS Pathog., 12, 2016, e1005854.
35. Van Doorslaer, K., Burk, R.D., Association between hTERT activation by HPV E6 proteins and oncogenic risk. Virology 433 (2012), 216–219.
36. Thomas, M., et al. Analysis of multiple HPV E6 PDZ interactions defines type-specific PDZ fingerprints that predict oncogenic potential. PLoS Pathog., 12, 2016, e1005766.
37. Wang, X., et al. microRNAs are biomarkers of oncogenic human papillomavirus infections. Proc. Natl. Acad. Sci. U. S. A. 111 (2014), 4262–4267.
38. Harden, M.E., et al. Modulation of microRNA-mRNA target pairs by human papillomavirus 16 oncoproteins. mBio, 8, 2017 e02170-16.
39. Honegger, A., et al. Dependence of intracellular and exosomal microRNAs on viral E6/E7 oncogene expression in HPV-positive tumor cells. PLoS Pathog., 11, 2015, e1004712.
40. Jung, H.M., et al. miR-375 activates p21 and suppresses telomerase activity by coordinately regulating HPV E6/E7, E6AP, CIP2A, and 14-3-3ζ. Mol. Cancer, 13, 2014, 80.
41. Duensing, S., Munger, K., Mechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteins. Int. J. Cancer 109 (2004), 157–162.
42. Burgers, W.A., et al. Viral oncoproteins target the DNA methyltransferases. Oncogene 26 (2007), 1650–1655.
43. Holland, D., et al. Activation of the enhancer of zeste homologue 2 gene by the human papillomavirus E7 oncoprotein. Cancer Res. 68 (2008), 9964–9972.
44. McLaughlin-Drubin, M.E., et al. Human papillomavirus E7 oncoprotein induces KDM6A and KDM6B histone demethylase expression and causes epigenetic reprogramming. Proc. Natl. Acad. Sci. U. S. A. 108 (2011), 2130–2135.
45. Sotlar, K., et al. Detection of high-risk human papillomavirus E6 and E7 oncogene transcripts in cervical scrapes by nested RT-polymerase chain reaction. J. Med. Virol. 74 (2004), 107–116.
46. Molden, T., et al. Comparison of human papillomavirus messenger RNA and DNA detection: a cross-sectional study of 4,136 women >30 years of age with a 2-year follow-up of high-grade squamous intraepithelial lesion. Cancer Epidemiol. Biomarkers Prev. 14 (2005), 367–372.
47. Fontecha, N., et al. Assessment of human papillomavirus E6/E7 oncogene expression as cervical disease biomarker. BMC Cancer, 16, 2016, 852.
48. Garcia-Carranca, A., et al. Interplay of viral and cellular proteins along the long control region of human papillomavirus type 18. J. Virol. 62 (1988), 4321–4330.
49. Butz, K., Hoppe-Seyler, F., Transcriptional control of human papillomavirus (HPV) oncogene expression: composition of the HPV type 18 upstream regulatory region. J. Virol. 67 (1993), 6476–6486.
50. Bernard, H.U., Regulatory elements in the viral genome. Virology 445 (2013), 197–204.
51. Bernard, B.A., et al. The human papillomavirus type 18 (HPV18) E2 gene product is a repressor of the HPV18 regulatory region in human keratinocytes. J. Virol. 63 (1989), 4317–4324.
52. McBride, A.A., Warburton, A., The role of integration in oncogenic progression of HPV-associated cancers. PLoS Pathog., 13, 2017, e1006211.
53. Häfner, N., et al. Integration of the HPV16 genome does not invariably result in high levels of viral oncogene transcripts. Oncogene 27 (2008), 1610–1617.
54. Chaiwongkot, A., et al. Differential methylation of E2 binding sites in episomal and integrated HPV 16 genomes in preinvasive and invasive cervical lesions. Int. J. Cancer 132 (2013), 2087–2094.
55. Dooley, K.E., et al. Tandemly integrated HPV16 can form a Brd 4-dependent super-enhancer-like element that drives transcription of viral oncogenes. mBio, 2016, 7 e01446-16.
56. Jeon, S., Lambert, P.F., Integration of human papillomavirus type 16 DNA into the human genome leads to increased stability of E6 and E7 mRNAs: implications for cervical carcinogenesis. Proc. Natl. Acad. Sci. U. S. A. 92 (1995), 1654–1658.
57. Schwabe, R.F., Jobin, C., The microbiome and cancer. Nat. Rev. Cancer 13 (2013), 800–812.
58. Mitra, A., et al. Cervical intraepithelial neoplasia disease progression is associated with increased vaginal microbiome diversity. Sci. Rep., 5, 2015, 16865.
59. Goodwin, E.C., DiMaio, D., Repression of human papillomavirus oncogenes in HeLa cervical carcinoma cells causes the orderly reactivation of dormant tumor suppressor pathways. Proc. Natl. Acad. Sci. U. S. A. 97 (2000), 12513–12518.
60. Goodwin, E.C., et al. Rapid induction of senescence in human cervical carcinoma cells. Proc. Natl. Acad. Sci. U. S. A. 97 (2000), 10978–10983.
61. Wells, S.I., et al. Papillomavirus E2 induces senescence in HPV-positive cells via pRB- and p21(CIP)-dependent pathways. EMBO J. 19 (2000), 5762–5771.
62. Hall, A.H., Alexander, K.A., RNA interference of human papillomavirus type 18 E6 and E7 induces senescence in HeLa cells. J. Virol. 77 (2003), 6066–6069.
63. Magaldi, T.G., et al. Primary human cervical carcinoma cells require human papillomavirus E6 and E7 expression for ongoing proliferation. Virology 422 (2012), 114–124.
64. Campisi, J., Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75 (2013), 685–705.
65. Hoppe-Seyler, K., et al. Induction of dormancy in hypoxic human papillomavirus-positive cancer cells. Proc. Natl. Acad. Sci. U. S. A. 114 (2017), E990–E998.
66. Honegger, A., et al. Silencing of human papillomavirus (HPV) E6/E7 oncogene expression affects both the contents and the amounts of extracellular microvesicles released from HPV-positive cancer cells. Int. J. Cancer 133 (2013), 1631–1642.
67. Blagosklonny, M.V., Geroconversion: irreversible step to cellular senescence. Cell Cycle 13 (2014), 3628–3635.
68. Spangle, J.M., Munger, K., The human papillomavirus type 16 E6 oncoprotein activates mTORC1 signaling and increases protein synthesis. J. Virol. 84 (2010), 9398–9407.
69. Stern, P.L., et al. Therapy of human papillomavirus-related disease. Vaccine 30:Suppl. 5 (2012), F71–F82.
70. Nizard, M., et al. Immunotherapy of HPV-associated head and neck cancer: critical parameters. Oncoimmunology, 2, 2013, e24534.
71. Skeate, J.G., et al. Current therapeutic vaccination and immunotherapy strategies for HPV-related diseases. Hum. Vaccin. Immunother. 12 (2016), 1418–1429.
72. Sterlinko Grm, H., et al. Inhibition of E6-induced degradation of its cellular substrates by novel blocking peptides. J. Mol. Biol. 335 (2004), 971–985.
73. Dymalla, S., et al. A novel peptide motif binding to and blocking the intracellular activity of the human papillomavirus E6 oncoprotein. J. Mol. Med. (Berl) 87 (2009), 321–331.
74. Ramirez, J., et al. Targeting the two oncogenic functional sites of the HPV E6 oncoprotein with a high-affinity bivalent ligand. Angew. Chem. Int. Ed. Engl. 54 (2015), 7958–7962.
75. Griffin, H., et al. Inhibition of papillomavirus protein function in cervical cancer cells by intrabody targeting. J. Mol. Biol. 355 (2006), 360–378.
76. Malecka, K.A., et al. Identification and characterization of small molecule human papillomavirus E6 inhibitors. ACS Chem. Biol. 9 (2014), 1603–1612.
77. Rietz, A., et al. Molecular probing of the HPV-16 E6 protein alpha helix binding groove with small molecule inhibitors. PLoS One, 11, 2016, e0149845.
78. + cells. Cell Death Dis., 7, 2016, 2060.
79. Zanier, K., et al. Structural basis for hijacking of cellular LxxLL motifs by papillomavirus E6 oncoproteins. Science 339 (2013), 694–698.
80. Zanier, K., et al. The E6AP binding pocket of the HPV16 E6 oncoprotein provides a docking site for a small inhibitory peptide unrelated to E6AP, indicating druggability of E6. PLoS One, 9, 2014, e112514.
81. Stutz, C., et al. Intracellular analysis of the interaction between the human papillomavirus type 16 E6 oncoprotein and inhibitory peptides. PLoS One, 10, 2015, e0132339.
82. Xue, W., et al. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature 445 (2007), 656–660.
83. Hellner, K., Münger, K., Human papillomaviruses as therapeutic targets in human cancer. J. Clin. Oncol. 29 (2011), 1785–1794.
84. Hoppe-Seyler, F., Hoppe-Seyler, K., Emerging topics in human tumor virology. Int. J. Cancer 129 (2011), 1289–1299.
85. Manzo-Merino, J., et al. HPV E6 oncoprotein as a potential therapeutic target in HPV related cancers. Expert Opin. Ther. Targets 17 (2013), 1357–1368.
86. Vaupel, P., Mayer, A., Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev. 26 (2007), 225–239.
87. Vaupel, P., et al. Detection and characterization of tumor hypoxia using pO2 histography. Antioxid. Redox Signal. 9 (2007), 1221–1235.
88. McKeown, S.R., Defining normoxia, physoxia and hypoxia in tumours-implications for treatment response. Br. J. Radiol., 87, 2014, 20130676.
89. Vaupel, P., et al. The impact of tumor biology on cancer treatment and multidisciplinary strategies. Molls, M., (eds.) Pathophysiology of Solid Tumors, 2009, Springer, 51–92.
90. Bensaad, K., Harris, A.L., Hypoxia and metabolism in cancer. Adv. Exp. Med. Biol. 772 (2014), 1–39.
91. Kumar, V., Gabrilovich, D.I., Hypoxia-inducible factors in regulation of immune responses in tumour microenvironment. Immunology 143 (2014), 512–519.
92. Noman, M.Z., et al. Hypoxia: a key player in antitumor immune response. A review in the theme: cellular responses to hypoxia. Am. J. Physiol. Cell Physiol. 309 (2015), C569–C579.
93. Stevanović, S., et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 356 (2017), 200–205.
94. Seiwert, T.Y., The concurrent chemoradiation paradigm – general principles. Nat. Clin. Pract. Oncol. 4 (2007), 86–100.
95. Wilson, W.R., Hay, M.P., Targeting hypoxia in cancer therapy. Nat. Rev. Cancer 11 (2011), 393–410.
96. Baran, N., Konopleva, M., Molecular pathways: hypoxia-activated prodrugs in cancer therapy. Clin. Cancer Res. 23 (2017), 2382–2390.
97. Roberts, N.J., et al. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci. Transl. Med., 6, 2014, 249ra111.
98. Felfoul, O., et al. Magneto-aerotactic bacteria deliver drug-containing nanoliposomes to tumour hypoxic regions. Nat. Nanotechnol. 11 (2016), 941–947.
99. Galluzzi, L., et al. Metabolic targets for cancer therapy. Nat. Rev. Drug Discov. 12 (2013), 829–846.
100. Zwerschke, W., et al. Modulation of type M2 pyruvate kinase activity by the human papillomavirus type 16 E7 oncoprotein. Proc. Natl. Acad. Sci. U. S. A. 96 (1999), 1291–1296.
101. Zeng, Q., et al. LKB1 inhibits HPV-associated cancer progression by targeting cellular metabolism. Oncogene 36 (2017), 1245–1255.
102. Vander Heiden, M.G., et al. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324 (2009), 1029–1033.
103. Bodily, J.M., et al. Human papillomavirus E7 enhances hypoxia-inducible factor 1-mediated transcription by inhibiting binding of histone deacetylases. Cancer Res. 71 (2011), 1187–1195.
104. Denko, N.C., Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat. Rev. Cancer 8 (2008), 705–713.
105. Röhrig, F., Schulze, A., The multifaceted roles of fatty acid synthesis in cancer. Nat. Rev. Cancer 16 (2016), 732–749.
106. Torti, S.V., Torti, F.M., Iron and cancer: more to be mined. Nat. Rev. Cancer 13 (2013), 342–355.