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Human papillomavirus targets the YAP1-LATS2 feedback loop to drive cervical cancer development

Abstract

Human papillomavirus (HPV) infection is very common in sexually active women, but cervical cancer only develops in a small fraction of HPV-infected women, suggesting that unknown intrinsic factors associated with the unique genetic/genomic background of the high-risk population play a critical role in cervical carcinogenesis. Although our previous studies have identified the hyperactivated YAP1 oncogene as a critical contributor to cervical cancer, the molecular mechanism by which YAP1 drives cervical cancer is unknown. In the present study, we found that although the hyperactivated YAP1 caused a malignant transformation of immortalized cervical epithelial cells, it induced cellular senescence in cultures of primary human cervical epithelial cells (HCvECs). However, the hyperactivated YAP1 induced malignant transformation of HCvECs in the presence of high-risk HPV E6/E7 proteins, suggesting that the hyperactivated YAP1 synergizes with HPV to initiate cervical cancer development. Our mechanistic studies demonstrate that YAP1, via up-regulating LATS2, formed a YAP1-LATS2 negative feedback loop in cervical epithelial cells to maintain homeostasis of cervical tissue. Intriguingly, we found that high-risk HPV targets LATS2 to disrupt the feedback loop leading to the malignant transformation of cervical epithelial cells. Finally, we report that mitomycin C, an FDA-approved drug that could upregulate LATS2 and drive cellular senescence in vitro and in vivo, induced a regression of cervical cancer in a pre-clinial animal model. Thus, high-risk HPV targeting the YAP1-LATS2 feedback loop represents a new mechanism of cervical cancer development.

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Fig. 1: Hyperactivation of YAP1 induced senescence of cultured primary human cervical epithelial cells (HCvECs).
Fig. 2: HPV rescued HCvECs from YAP1-induced senescence.
Fig. 3: Synergistic combination of HPV infection and YAP1 hyperactivation induced tumorigenesis.
Fig. 4: Hyperactivated YAP1-induced overexpression of LATS2 in HCvEC cells contributes to the observed senescent phenotype.
Fig. 5: LATS2 is involved in the replication-induced senescence of human cervical epithelial cell.
Fig. 6: HPV E6/E7 target LATS2 in cervical epithelial cells.
Fig. 7: Overexpression of LATS2 also inhibited proliferation of cancerous cervical epithelial cells.
Fig. 8: Mitomycin (MMC) up-regulated LATS2 to induce senescence in cervical cancer cells.
Fig. 9: MMC up-regulated LATS2 expression and blocked cervical cancer progression in vivo.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    PubMed  Google Scholar 

  2. Arbyn M, Weiderpass E, Bruni L, de Sanjosé S, Saraiya M, Ferlay J, et al. Estimates of incidence and mortality of cervical cancer in 2018: a worldwide analysis. Lancet Glob Health. 2019;8:e191–e203.

    PubMed  PubMed Central  Article  Google Scholar 

  3. Shah R, Nwankwo C, Kwon Y, Corman SL. Economic and humanistic burden of cervical cancer in the united states: results from a nationally representative survey. J Women’s Health (Larchmt). 2020;29:799–805.

    Article  Google Scholar 

  4. Stelzle D, Stelzle D, Tanaka LF, Lee KK, Ibrahim Khalil A, Baussano I, et al. Estimates of the global burden of cervical cancer associated with HIV. Lancet Glob Health 2021;9:e161–169.

    PubMed  Article  Google Scholar 

  5. Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol. 2002;55:244–65.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–19.

    CAS  PubMed  Article  Google Scholar 

  7. Molano M, Van den Brule A, Plummer M, Weiderpass E, Posso H, Arslan A, et al. Determinants of clearance of human papillomavirus infections in Colombian women with normal cytology: a population-based, 5-year follow-up study. Am J Epidemiol. 2003;158:486–94.

    PubMed  Article  Google Scholar 

  8. Perez-Plasencia C, Duenas-Gonzalez A, Alatorre-Tavera B. Second hit in cervical carcinogenesis process: involvement of wnt/beta-catenin pathway. Int Arch Med. 2008;1:10.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  9. Howlader N, N.A., Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, et al. (eds). SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. 2012, Based on November 2011 SEER data submission, posted to the SEER web site, April 2012.

  10. Koutsky L. Epidemiology of genital human papillomavirus infection. Am J Med. 1997;102:3–8.

    CAS  PubMed  Article  Google Scholar 

  11. Kulasingam SL, Hughes JP, Kiviat NB, Mao C, Weiss NS, Kuypers JM, et al. Evaluation of human papillomavirus testing in primary screening for cervical abnormalities: comparison of sensitivity, specificity, and frequency of referral. JAMA. 2002;288:1749–57.

    PubMed  Article  Google Scholar 

  12. Xing B, Guo J, Sheng Y, Wu G, Zhao Y. Human papillomavirus-negative cervical cancer: a comprehensive review. Front Oncol. 2021;10:606335.

    PubMed  PubMed Central  Article  Google Scholar 

  13. Cancer Genome Atlas Research Network. Integrated genomic and molecular characterization of cervical cancer. Nature 2017;543:378–84.

    Article  CAS  Google Scholar 

  14. He C, Mao D, Hua G, Lv X, Chen X, Angeletti PC, et al. The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. EMBO Mol Med. 2015;7:1426–49.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. He C, Lv X, Huang C, Angeletti PC, Hua G, Dong J, et al. A human papillomavirus-independent cervical cancer animal model reveals unconventional mechanisms of cervical carcinogenesis. Cell Rep. 2019;26:2636–.e5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. Wang C, Davis JS. At the center of cervical carcinogenesis: synergism between high-risk HPV and the hyperactivated YAP1. Mol Cell Oncol. 2019;6:e1612677.

    PubMed  PubMed Central  Article  Google Scholar 

  17. Mo JS, Park HW, Guan KL. The Hippo signaling pathway in stem cell biology and cancer. EMBO Rep. 2014;15:642–56.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Pan D. The hippo signaling pathway in development and cancer. Developmental cell. 2010;19:491–505.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. Zanconato F, Cordenonsi M, Piccolo S. YAP/TAZ at the Roots of Cancer. Cancer cell. 2016;29:783–803.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Dey A, Varelas X, Guan KL. Targeting the Hippo pathway in cancer, fibrosis, wound healing, and regenerative medicine. Nat Rev Drug Disco. 2020;19:480–94.

    CAS  Article  Google Scholar 

  21. Moya IM, Halder G. Hippo-YAP/TAZ Signaling in organ regeneration and regenerative medicine. Nat Rev Mol Cell Biol. 2019;20:211–26.

    CAS  PubMed  Article  Google Scholar 

  22. Dong J, Feldmann G, Huang J, Wu S, Zhang N, Comerford SA, et al. Elucidation of a universal size-control mechanism in Drosophila and mammals. Cell 2007;130:1120–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Moroishi T, Park HW, Qin B, Chen Q, Meng Z, Plouffe SW, et al. A YAP/TAZ-induced feedback mechanism regulates Hippo pathway homeostasis. Genes Dev. 2015;29:1271–84.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Dai X, Liu H, Shen S, Guo X, Yan H, Ji X, et al. YAP activates the Hippo pathway in a negative feedback loop. Cell Res. 2015;25:1175–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  25. Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:pl1.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  26. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Disco. 2012;2:401–4.

    Article  Google Scholar 

  27. Campisi J. Cellular senescence as a tumor-suppressor mechanism. Trends Cell Biol. 2001;11:S27–31.

    CAS  PubMed  Article  Google Scholar 

  28. Braig M, Schmitt CA. Oncogene-induced senescence: putting the brakes on tumor development. Cancer Res. 2006;66:2881–4.

    CAS  PubMed  Article  Google Scholar 

  29. Braig M, Lee S, Loddenkemper C, Rudolph C, Peters AH, Schlegelberger B, et al. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature. 2005;436:660–5.

    CAS  PubMed  Article  Google Scholar 

  30. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 2005;436:725–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Turrigiano G. Homeostatic signaling: the positive side of negative feedback. Curr Opin Neurobiol. 2007;17:318–24.

    CAS  PubMed  Article  Google Scholar 

  32. Modell H, Cliff W, Michael J, McFarland J, Wenderoth MP, Wright A. A physiologist’s view of homeostasis. Adv Physiol Educ. 2015;39:259–66.

    PubMed  PubMed Central  Article  Google Scholar 

  33. Brandman O, Meyer T. Feedback loops shape cellular signals in space and time. Science 2008;322:390–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Billman GE. Homeostasis: The Underappreciated and Far Too Often Ignored Central Organizing Principle of Physiology. Front Physiol. 2020;11:200.

    PubMed  PubMed Central  Article  Google Scholar 

  35. Ferrell JE Jr. Feedback loops and reciprocal regulation: recurring motifs in the systems biology of the cell cycle. Curr Opin Cell Biol. 2013;25:676–86.

    PubMed  Article  CAS  Google Scholar 

  36. Schiffman MH, Castle P. Epidemiologic studies of a necessary causal risk factor: human papillomavirus infection and cervical neoplasia. J Natl Cancer Inst. 2003;95:E2.

    PubMed  Article  Google Scholar 

  37. Castellsague X, Diaz M, de Sanjose S, Munoz N, Herrero R, Franceschi S, et al. Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. J Natl Cancer Inst. 2006;98:303–15.

    PubMed  Article  Google Scholar 

  38. Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM. The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 1990;63:1129–36.

    CAS  PubMed  Article  Google Scholar 

  39. Dyson N, Howley PM, Munger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989;243:934–7.

    CAS  PubMed  Article  Google Scholar 

  40. Boyer SN, Wazer DE, Band V. E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Res. 1996;56:4620–4.

    CAS  PubMed  Google Scholar 

  41. Castellsagué X. Natural history and epidemiology of HPV infection and cervical cancer. Gynecol Oncol. 2008;110:S4–7.

    PubMed  Article  Google Scholar 

  42. Woodman CB, Collins SI, Young LS. The natural history of cervical HPV infection: unresolved issues. Nat Rev Cancer. 2007;7:11–22.

    CAS  PubMed  Article  Google Scholar 

  43. Harvey M, Vogel H, Lee EY, Bradley A, Donehower LA. Mice deficient in both p53 and Rb develop tumors primarily of endocrine origin. Cancer Res. 1995;55:1146–51.

    CAS  PubMed  Google Scholar 

  44. Riley RR, Duensing S, Brake T, Münger K, Lambert PF, Arbeit JM. Dissection of human papillomavirus E6 and E7 function in transgenic mouse models of cervical carcinogenesis. Cancer Res. 2003;63:4862–71.

    CAS  PubMed  Google Scholar 

  45. Brake T, Lambert PF. Estrogen contributes to the onset, persistence, and malignant progression of cervical cancer in a human papillomavirus-transgenic mouse model. Proc Natl Acad Sci USA. 2005;102:2490–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Chung S, Wiedmeyer K, Shai A, Korach KS, Lambert PF. Requirement for estrogen receptor alpha in a mouse model for human papillomavirus-associated cervical cancer. Cancer Res. 2008;68:9928–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Chung SH, Franceschi S, Lambert PF. Estrogen and ERalpha: culprits in cervical cancer? Trends Endocrinol Metab. 2010;21:504–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. Lee S, Schmitt CA. The dynamic nature of senescence in cancer. Nat Cell Biol. 2019;21:94–101.

    CAS  PubMed  Article  Google Scholar 

  49. Wyld L, Bellantuono I, Tchkonia T, Morgan J, Turner O, Foss F, et al. Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies. Cancers (Basel). 2020;12:2134.

    CAS  Article  Google Scholar 

  50. He C, Lv X, Huang C, Hua G, Ma B, Chen X, et al. YAP1-LATS2 feedback loop dictates senescent or malignant cell fate to maintain tissue homeostasis. EMBO Rep. 2019;20:e44948.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  51. Liu XL, Ding J, Meng LH. Oncogene-induced senescence: a double-edged sword in cancer. Acta Pharm Sin 2018;39:1553–8.

    CAS  Article  Google Scholar 

  52. Li X, Xu H, Xu C, Lin M, Song X, Yi F, et al. The Yin-Yang of DNA Damage Response: Roles in Tumorigenesis and Cellular Senescence. Int J Mol Sci. 2013;14:2431–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, et al. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 2005;436:725–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Childs BG, Durik M, Baker DJ, van Deursen JM. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat Med. 2015;21:1424–35.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Sherr CJ, McCormic F. The RB and p53 pathways in cancer. Cancer cell. 2002;2:103–12.

    CAS  PubMed  Article  Google Scholar 

  56. Schmitt CA, Fridman JS, Yang M, Lee S, Baranov E, Hoffman RM, et al. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy. Cell 2002;109:335–46.

    CAS  PubMed  Article  Google Scholar 

  57. Courtois-Cox S, Jones SL, Cichowski K. Many roads lead to oncogene-induced senescence. Oncogene 2008;27:2801–9.

    CAS  PubMed  Article  Google Scholar 

  58. Fu D, Lv X, Hua G, He C, Dong J, Lele SM, et al. YAP regulates cell proliferation, migration, and steroidogenesis in adult granulosa cell tumors. Endocr Relat Cancer. 2014;21:297–231.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Wang C, Lv X, He C, Hua G, Tsai MY, Davis JS. The G-protein-coupled estrogen receptor agonist G-1 suppresses proliferation of ovarian cancer cells by blocking tubulin polymerization. Cell Death Dis. 2013;4:e869.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Hua G, He C, Lv X, Fan L, Wang C, Remmenga SW, et al. The four and a half LIM domains 2 (FHL2) regulates ovarian granulosa cell tumor progression via controlling AKT1 transcription. Cell Death Dis. 2016;7:e2297.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Lv X, He C, Huang C, Hua G, Wang Z, Remmenga SW, et al. G-1 Inhibits Breast Cancer Cell Growth via Targeting Colchicine-Binding Site of Tubulin to Interfere with Microtubule Assembly. Mol Cancer Ther. 2017;16:1080–91.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Wang C, Roy SK. Expression of E-cadherin and N-cadherin in perinatal hamster ovary: possible involvement in primordial follicle formation and regulation by follicle-stimulating hormone. Endocrinology 2010;151:2319–30.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Zhang Y, Park C, Bennett C, Thornton M, Kim D. Rapid and accurate alignment of nucleotide conversion sequencing reads with HISAT-3N. Genome Res. 2021;31:1290–5.

    PubMed Central  Article  Google Scholar 

  64. Trapnell C, Williams BA, Pertea G, Mortazavi A, Kwan G, van Baren MJ, et al. Transcript assembly and quantification by RNA-Seq reveals unannotated transcripts and isoform switching during cell differentiation. Nat Biotechnol. 2010;28:511–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 2010;26:139–40.

    CAS  PubMed  Article  Google Scholar 

  66. Pyeon D, Newton MA, Lambert PF, den Boon JA, Sengupta S, Marsit CJ, et al. Fundamental differences in cell cycle deregulation in human papillomavirus-positive and human papillomavirus-negative head/neck and cervical cancers. Cancer Res. 2007;67:4605–19.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Rosty C, Sheffer M, Tsafrir D, Stransky N, Tsafrir I, Peter M, et al. Identification of a proliferation gene cluster associated with HPV E6/E7 expression level and viral DNA load in invasive cervical carcinoma. Oncogene 2005;24:7094–104.

    CAS  PubMed  Article  Google Scholar 

  68. Korotkevich G, Sukhov V, Budin N, Shpak B, Artyomov MN, Sergushichev A. Fast gene set enrichment analysis. BioRxiv 2021;060012.

  69. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. Liberzon A, Subramanian A, Pinchback R, Thorvaldsdóttir H, Tamayo P, Mesirov JP. Molecular signatures database (MSigDB) 3.0. Bioinformatics. 2011;27:1739–40.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16:284–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinformatics. 2016;32:2847–9.

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

This work was supported by the National Cancer Institute/National Institute of Health (1R01CA197976, 1R01CA201500), the Vincent Memorial Hospital Foundation/Vincent Center for Reproductive Biology, Colleen’s Dream Foundation (no number), and the Ruggles Family Foundation. JSD is the recipient of a Veterans Administration Senior Research Career Scientist Award. BR was supported by the Nile Albright Research Foundation.

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CH contributed to the experimental design, performance, data collection/analysis, and manuscript preparation. XLv contributed to experimental design and performed tumorigenic experiments. PC and JL contribute to experimental design, establishment of new cellular models, RNA-sequencing, and bioinformatic analyses. CHe contributed to experimental design and establishment of new cellular models. JD contributes to the construction of YAP1-expressing vectors. LC, MLM, and HW conducted IHC and real-time PCR analyses. JSD and BRR contributed to results discussion and manuscript review. CW conceived the original idea, supervised the studies, and contributed to experimental design, data analysis, and manuscript preparation.

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Correspondence to Cheng Wang.

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Huang, C., Lv, X., Chen, P. et al. Human papillomavirus targets the YAP1-LATS2 feedback loop to drive cervical cancer development. Oncogene 41, 3761–3777 (2022). https://doi.org/10.1038/s41388-022-02390-y

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