Role of Yes-associated protein [YAP]- A Key Hippo Component in the Onset and Progression of Oral Squamous Cell Carcinoma
Background: Tumorigenesis is an abnormal growth of cells within the body, usually induced by abnormal proliferation of the stem cells or abnormal apoptosis, the usual disturbance in the cell cycle. Various signalling pathways play a role in the cell cycle, which, when altered, result in abnormal cell proliferation and thus cancerogenesis. One such important pathway is the Hippo pathway, which plays a major role in controlling the organ's size. Dysregulation in the components of the hippo pathway, causing cancers, has been studied in the literature in various cancers such as breast cancer, liver cancer, colorectal cancer, and liver cancer.Aim: This review focuses on the role of Yes-associated protein (YAP), a key effector of the Hippo pathway, in the onset and progression of oral squamous cell carcinoma (OSCC). We summarize recent achievements in understanding YAP's mechanisms in OSCC pathogenesis and discuss its potential as a therapeutic target.
Methods: A comprehensive literature search was conducted in PubMed, Scopus, and Web of Science for articles published between January 2010 and March 2025, using the terms "YAP," "Yes-associated protein," "Hippo pathway," "oral squamous cell carcinoma," and "oral cancer." Inclusion criteria were original research and review articles in English focusing on YAP in OSCC or oral precancerous lesions. Exclusion criteria included non-English articles, case reports, and studies not involving OSCC or YAP.
Conclusions: YAP plays a vital role in malignant transformation, with its dysfunction initiating tumor growth factor expression and being associated with tumor growth and metastasis in OSCC. Understanding YAP's role in the onset and progression of OSCC may identify specific targets for anti-cancer therapy.
1. Johnson DE, Burtness B, Leemans CR, Lui VW, Bauman JE, Grandis JR. Head and neck squamous cell carcinoma. Nat Rev Dis Primers. 2020;6(1):92.
2. Mesgari H, Esmaelian S, Nasiri K, Ghasemzadeh S, Doroudgar P, Payandeh Z. Epigenetic regulation in oral squamous cell carcinoma microenvironment: a comprehensive review. Cancers (Basel). 2023;15(23):5600.
3. Ehmer U, Sage J. Control of proliferation and cancer growth by the Hippo signaling pathway. Mol Cancer Res. 2016;14(2):127-40.
4. Ma S, Meng Z, Chen R, Guan KL. The Hippo pathway: biology and pathophysiology. Annu Rev Biochem. 2019;88(1):577-604.
5. Chen YA, Lu CY, Cheng TY, Pan SH, Chen HF, Chang NS. WW domain-containing proteins YAP and TAZ in the hippo pathway as key regulators in stemness maintenance, tissue homeostasis, and tumorigenesis. Front Oncol. 2019;9:60.
6. Pan D. The unfolding of the Hippo signaling pathway. Dev Bio. 2022;487:1-9.
7. Watt KI, Harvey KF, Gregorevic P. Regulation of tissue growth by the mammalian Hippo signaling pathway. Front Physiol. 2017;8:942.
8. Huang H, Wu W, Zhang L, Liu XY. Drosophila ste-20 family protein kinase, hippo, modulates fat cell proliferation. PLoS One. 2013;8(4):e61740.
9. Avruch J, Zhou D, Fitamant J, Bardeesy N, Mou F, Barrufet LR. Protein kinases of the Hippo pathway: regulation and substrates. Semi Cell Dev Bio. 2012;23(7);770-84.
10. Harvey K, Tapon N. The Salvador–Warts–Hippo pathway— an emerging tumor-suppressor network. Nat Rev Cancer. 2007;7(3):182-91.
11. Zhu C, Li L, Zhao B. The regulation and function of YAP transcription co-activator. Acta Biochim Biophys Sin (Shanghai). 2015;47(1):16-28.
12. Currey L, Thor S, Piper M. TEAD family transcription factors in development and disease. Development. 2021;148(12):dev196675.
13. Wang M, Dai M, Wang D, Xiong W, Zeng Z, Guo C. The regulatory networks of the Hippo signaling pathway in cancer development. J Cancer. 2021;12(20):6216-30.
14. Pocaterra A, Romani P, Dupont S. YAP/TAZ functions and their regulation at a glance. J Cell Sci. 2020;133(2):jcs230425.
15. Morciano G, Vezzani B, Missiroli S, Boncompagni C, Pinton P, Giorgi C. An updated understanding of the role of YAP in driving oncogenic responses. Cancers (Basel). 2021;13(12):3100.
16. Driskill JH, Pan D. Control of stem cell renewal and fate by YAP and TAZ. Nat Rev Mol Cell Bio. 2023;24(12):895-911.
17. Ahmad US, Saravanan KA, Wan HO. The role of YAP in the control of the metastatic potential of oral cancer. Oncol Res. 2021;29(6):377-91.
18. Sudol M, Shields DC, Farooq A. Structures of YAP protein domains reveal promising targets for development of new cancer drugs. Semin Cell Dev Bio. 2012;23(7):827-33.
19. Tian W, Yu J, Tomchick DR, Pan D, Luo X. Structural and functional analysis of the YAP-binding domain of human TEAD2. Proc Natl Acad Sci U S A. 2010;107(16):7293-8.
20. Chen L, Chan SW, Zhang X, Walsh M, Lim CJ, Hong W, et al. Structural basis of YAP recognition by TEAD4 in the hippo pathway. Genes Dev. 2010;24(3):290-300.
21. Li Z, Zhao B, Wang P, Chen F, Dong Z, Yang H, Guan KL, Xu Y. Structural insights into the YAP and TEAD complex. Genes Dev. 2010;24(3):235-40.
22. Yu FX, Guan KL. The hippo pathway: regulators and regulations. Genes Dev. 2013;27(4):355-71.
23. Abylkassov R, Xie Y. Role of Yes-associated protein in cancer: an update. Oncol Lett. 2016;12(4):2277-82.
24. Basu S, Totty NF, Irwin MS, Sudol M, Downward J. Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. Mol Cell. 2003;11(1):11-23.
25. Kwon H, Kim J, Jho EH. Role of the Hippo pathway and mechanisms for controlling cellular localization of YAP/ TAZ. The FEBS J. 2022;289(19):5798-818.
26. Zou R, Xu Y, Feng Y, Shen M, Yuan F, Yuan Y. YAP nuclear-cytoplasmic translocation is regulated by mechanical signaling, protein modification, and metabolism. Cell Biol Int. 2020;44(7):1416-25.
27. Wang D, Zhang Y, Xu X, Wu J, Peng Y, Li J, et al. YAP promotes the activation of NLRP3 inflammasome via blocking K27-linked polyubiquitination of NLRP3. Nat Commun. 2021;12(1):2674.
28. Sun X, Ding Y, Zhan M, Li Y, Gao D, Wang G, et al. Usp7 regulates Hippo pathway through deubiquitinating the transcriptional coactivator Yorkie. Nat Commun. 2019; 10(1):411.
29. Liu Z, Li J, Ding Y, Ma M, Chen J, Lei W, et al. USP49 mediates tumor progression and poor prognosis through a YAP1-dependent feedback loop in gastric cancer. Oncogene. 2022;41(18):2555-70.
30. Shin E, Kwon Y, Jung E, Kim YJ, Kim C, Hong S, et al. TM4SF19 controls GABP-dependent YAP transcription in head and neck cancer under oxidative stress conditions. Proc Natl Acad Sci U S A. 2024;121(7):e2314346121.
31. Trejo-Solis C, Escamilla-Ramirez A, Jimenez-Farfan D, Castillo-Rodriguez RA, Flores-Najera A, Cruz-Salgado A. Crosstalk of the Wnt/β-catenin signaling pathway in the induction of apoptosis on cancer cells. Pharmaceuticals (Basel). 2021;14(9):871.
32. Samji P, Rajendran MK, Warrier VP, Ganesh A, Devarajan K. Regulation of Hippo signaling pathway in cancer: A microRNA perspective. Cell Signal. 2021;78:109858.
33. Xu X, Chen X, Xu MU, Liu X, Pan B, Qin J, et al. miR- 375-3p suppresses tumorigenesis and partially reverses chemoresistance by targeting YAP1 and SP1 in colorectal cancer cells. Aging (Albany NY). 2019;11(18):7357-85.
34. Wen B, Zhu R, Jin H, Zhao K. Differential expression and role of miR-200 family in multiple tumors. Anal Biochem. 2021;626:114243
35. Zou H, Luo J, Guo Y, Liu Y, Wang Y, Deng L, et al. RNAbinding protein complex LIN28/MSI2 enhances cancer stem cell-like properties by modulating Hippo-YAP1 signaling and independently of Let-7. Oncogene. 2022;41(11):1657-72.
36. Wang HY, Long QY, Tang SB, Xiao Q, Gao C, Zhao QY, et al. Histone demethylase KDM3A is required for enhancer activation of hippo target genes in colorectal cancer. Nucleic Acids Res. 2019;47(5):2349-64.
37. Tranchant R, Quetel L, Montagne F, De Wolf J, Meiller C, De Koning L, et al. Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma. Lung Cancer. 2018;126: 15-24.
38. Chang L, Azzolin L, Di Biagio D, Zanconato F, Battilana G, Lucon Xiccato R, et al. The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ. Nature. 2018;563(7730):265-9.
39. Mo C, You W, Rao Y, Lin Z, Wang S, He T, et al. Epigenetic regulation of DNA repair gene program by Hippo/YAP1- TET1 axis mediates sorafenib resistance in HCC. Cell Mol Life Sci. 2024;81(1):1-7.
40. Sorrentino G, Ruggeri N, Specchia V, Cordenonsi M, Mano M, Dupont S, et al. Metabolic control of YAP and TAZ by the mevalonate pathway. Nat Cell Biol. 2014;16(4):357-66.
41. Liu L, Liu M, Xie D, Liu X, Yan H. Role of the extracellular matrix and YAP/TAZ in cell reprogramming. Differentiation. 2021;122:1-6.
42. Shao Q, Xu J, Deng R, Wei W, Zhou B, Yue C, et al. The expressions of YAP1, β-catenin and survivin in colon cancer tissues and their clinical significance. Int J Clin Exp Pathol. 2018;11(12):6032-8.
43. Seo Y, Park SY, Kim HS, Nam JS. The hippo–yap signaling as guardian in the pool of intestinal stem cells. Biomedicines. 2020;8(12):560.
44. Mouillet-Richard S, Laurent-Puig P. YAP/TAZ signalling in colorectal cancer: Lessons from consensus molecular subtypes. Cancers (Basel). 2020;12(11):3160.
45. Mia MM, Singh MK. New insights into Hippo/YAP signaling in fibrotic diseases. Cells. 2022;11(13):2065.
46. Park I, Lee Y, Kim JH, Bae SJ, Ahn SG, Jeong J, et al. YAP1 expression in HR+ HER2- breast cancer: 21-gene recurrence score analysis and public dataset validation. Cancers (Basel). 2023;15(20):5034.
47. Yuan M, Tomlinson V, Lara R, Holliday D, Chelala C, Harada T, et al. Yes-associated protein (YAP) functions as a tumor suppressor in breast. Cell Death Differ. 2008;15(11):1752-9.
48. Bertini E, Oka T, Sudol M, Strano S, Blandino G. YAP: at the crossroad between transformation and tumor suppression. Cell Cycle. 2009;8(1):49-57.
49. Ghantous Y, Schussel JL, Brait M. Tobacco and alcohol induced epigenetic changes in oral carcinoma. Curr Opin Oncol. 2018;30(3):152-8
50. Segrelles C, Paramio JM, Lorz C. The transcriptional coactivator YAP: a new player in head and neck cancer. Oral Oncol. 2018;86:25-32.
51. Santos-de-Frutos K, Segrelles C, Lorz C. Hippo pathway and YAP signaling alterations in squamous cancer of the head and neck. J Clin Med. 2019;8(12):2131.
52. Li SY, Hu JA, Wang HM. Expression of Yes-associated protein 1 gene and protein in oral squamous cell carcinoma. Chinese Med J. 2013;126(4):655-8.
53. Hiemer SE, Zhang L, Kartha VK, Packer TS, Almershed M, Noonan V, et al. A YAP/TAZ-regulated molecular signature is associated with oral squamous cell carcinoma. Mol Cancer Res. 2015;13(6):957-68.
54. Hasegawa K, Fujii S, Matsumoto S, Tajiri Y, Kikuchi A, Kiyoshima T. YAP signaling induces PIEZO1 to promote oral squamous cell carcinoma cell proliferation. J Pathol. 2021;253(1):80-93.
55. Ge L, Smail M, Meng W, Shyr Y, Ye F, Fan KH, et al. Yesassociated protein expression in head and neck squamous cell carcinoma nodal metastasis. PLoS One. 2011;6(11): e27529.
56. Qi L, Shi C, Li J, Xu S, Han Y, Li J, et al. Yes-associated protein promotes cell migration via activating Wiskott Aldrich syndrome protein family member 1 in oral squamous cell carcinoma. J Oral Pathol Med. 2019;48(4):290-8.
57. Szelachowska J, Donizy P, Ratajczak Wielgomas K, Halon A, Zielecka Debska D, Lichon K, et al. The effect of YAP expression in tumor cells and tumor stroma on the prognosis of patients with squamous cell carcinoma of the oral cavity floor and oral surface of the tongue. Oncol Lett. 2019;18(4):3561-70.
58. Ono S, Nakano K, Takabatake K, Kawai H, Nagatsuka H. Immunohistochemistry of YAP and dNp63 and survival analysis of patients bearing precancerous lesion and oral squamous cell carcinoma. Int J Med Sci. 2019;16(5):766.
59. Zhang L, Ye DX, Pan HY, Wei KJ, Wang LZ, Wang XD, et al. Yes-associated protein promotes cell proliferation by activating Fos related activator-1 in oral squamous cell carcinoma. Oral Oncol. 2011;47(8):693-7.
60. Omori H, Nishio M, Masuda M, Miyachi Y, Ueda F, Nakano T, et al. YAP1 is a potent driver of the onset and progression of oral squamous cell carcinoma. Sci Adv. 2020;6(12):eaay3324.
61. Cunningham R, Hansen CG. The hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer. Clin Sci. 2022;136(3):197-222.
62. Tang Z, Ma Q, Wang L, Liu C, Gao H, Yang Z, et al. A brief review: some compounds targeting YAP against malignancies. Future Oncol. 2019;15(13):1535-43.
63. Ardestani A, Maedler K. The hippo signaling pathway in pancreatic β-cells: Functions and regulations. Endocr Rev. 2018;39(1):21-35