Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

Tissue inhibitor of metalloproteinase-1 promotes cell proliferation through YAP/TAZ activation in cancer

Oncogene volume 37, pages 263–270 (2018)Cite this article

Subjects

Abstract

Tissue inhibitor of metalloproteinase-1 (TIMP-1), a member of the TIMP family (TIMP-1 to 4), is highly expressed in various types of cancer and forms a complex with its receptor CD63 and Integrin β1. However, the precise oncogenic mechanism of TIMP-1 remains unclear. Yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ) are transcription co-activators enhancing the transcription of specific genes related to cell proliferation. But the mechanism of aberrant YAP/TAZ activation in cancer is not fully understood. Here, we showed that TIMP-1 activates YAP/TAZ as novel downstream targets to promote cell proliferation. The TIMP-1-CD63-Integrin β1 axis activates Src and promotes RhoA-mediated F-actin assembly, leading to LATS1/2 inactivation. This results in under-phosphorylation, protein stabilization and nuclear translocation of YAP/TAZ (YAP/TAZ activation); CTGF production; and cell proliferation. Furthermore, the TIMP-1-YAP/TAZ axis is aberrantly activated in various types of cancer cells or tissues. TIMP-1 knockdown inhibits cell proliferation through YAP/TAZ inactivation in cancer cells. This study found that TIMP-1 accelerates cell proliferation through YAP/TAZ activation in cancer, and suggests the TIMP-1-YAP/TAZ axis may be a novel potential drug target for cancer patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Dechaphunkul A, Phukaoloun M, Kanjanapradit K, Graham K, Ghosh S, Santos C et al. Prognostic significance of tissue inhibitor of metalloproteinase-1 in breast cancer. Int J Breast Cancer 2012; 2012: 10.

    Article  Google Scholar 

  2. Oh WK, Vargas R, Jacobus S, Leitzel K, Regan MM, Hamer P et al. Elevated plasma tissue inhibitor of metalloproteinase-1 levels predict decreased survival in castration-resistant prostate cancer patients. Cancer 2011; 117: 517–525.

    Article  CAS  Google Scholar 

  3. Xia Y, Yeddula N, Leblanc M, Ke E, Zhang Y, Oldfield E et al. Reduced cell proliferation by IKK2 depletion in a mouse lung-cancer model. Nat Cell Biol 2012; 14: 257–265.

    Article  CAS  Google Scholar 

  4. Grunnet M, Mau-Sørensen M, Brünner N . Tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker in gastric cancer: a review. Scand J Gastroenterol 2013; 48: 899–905.

    Article  Google Scholar 

  5. Toricelli M, Melo FH, Peres GB, Silva DC, Jasiulionis MG . Timp1 interacts with beta-1 integrin and CD63 along melanoma genesis and confers anoikis resistance by activating PI3-k signaling pathway independently of Akt phosphorylation. Mol Cancer 2013; 12: 22.

    Article  CAS  Google Scholar 

  6. Terpos E, Dimopoulos MA, Shrivastava V, Leitzel K, Christoulas D, Migkou M et al. High levels of serum TIMP-1 correlate with advanced disease and predict for poor survival in patients with multiple myeloma treated with novel agents. Leuk Res 2010; 34: 399–402.

    Article  CAS  Google Scholar 

  7. Ma J, Wang J, Fan W, Pu X, Zhang D, Fan C et al. Upregulated TIMP-1 correlates with poor prognosis of laryngeal squamous cell carcinoma. Int J Clin Exp Pathol 2013; 7: 246–254.

    PubMed  PubMed Central  Google Scholar 

  8. Crocker M, Ashley S, Giddings I, Petrik V, Hardcastle A, Aherne W et al. Serum angiogenic profile of patients with glioblastoma identifies distinct tumor subtypes and shows that TIMP-1 is a prognostic factor. Neuro Oncol 2011; 13: 99–108.

    Article  CAS  Google Scholar 

  9. Kozłowski M, Laudański W, Mroczko B, Szmitkowski M, Milewski R, Lapuć G . Serum tissue inhibitor of metalloproteinase 1 (TIMP-1) and vascular endothelial growth factor A (VEGF-A) are associated with prognosis in esophageal cancer patients. Adv Med Sci 2013; 58: 227–234.

    Article  Google Scholar 

  10. Song G, Xu S, Zhang H, Wang Y, Xiao C, Jiang T et al. TIMP1 is a prognostic marker for the progression and metastasis of colon cancer through FAK-PI3K/AKT and MAPK pathway. J Exp Clin Cancer Res 2016; 35: 148.

    Article  Google Scholar 

  11. Jung KK, Liu XW, Chirco R, Fridman R, Kim HR . Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. EMBO J 2006; 25: 3934–3942.

    Article  CAS  Google Scholar 

  12. Chirco R, Liu XW, Jung KK, Kim HR . Novel functions of TIMPs in cell signaling. Cancer Metast Rev 2006; 25: 99–113.

    Article  CAS  Google Scholar 

  13. Moroishi T, Hansen CG, Guan KL . The emerging roles of YAP and TAZ in cancer. Nat Rev Cancer 2015; 15: 73–79.

    Article  CAS  Google Scholar 

  14. Park HW, Guan KL . Regulation of the hippo pathway and implications for anticancer drug development. Trends Pharmacol Sci 2013; 34: 581–589.

    Article  CAS  Google Scholar 

  15. Yu FX, Zhao B, Panupinthu N, Jewell JL, Lian I, Wang LH et al. Regulation of the Hippo-YAP pathway by G-protein-coupled receptor signaling. Cell 2012; 150: 780–791.

    Article  CAS  Google Scholar 

  16. Liu X, Li H, Rajurkar M, Li Q, Cotton JL, Ou J et al. Tead and AP1 coordinate transcription and motility. Cell Rep 2016; 14: 1169–1180.

    Article  CAS  Google Scholar 

  17. Zhao B, Ye X, Yu J, Li L, Li W, Li S et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev 2008; 22: 1962–1971.

    Article  CAS  Google Scholar 

  18. Piccolo S, Dupont S, Cordenonsi M . The biology of YAP/TAZ: hippo signaling and beyond. Physiol Rev 2014; 94: 1287–1312.

    Article  CAS  Google Scholar 

  19. Strano S, Monti O, Pediconi N, Baccarini A, Fontemaggi G, Lapi E et al. The transcriptional coactivator Yes-associated protein drives p73 gene-target specificity in response to DNA Damage. Mol Cell 2005; 18: 447–459.

    Article  CAS  Google Scholar 

  20. Rosenbluh J, Nijihawan D, Cox AG, Li X, Neal JT, Schafer EJ et al. β-catenin-driven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell 2012; 151: 1457–1473.

    Article  CAS  Google Scholar 

  21. Yagi R, Chen LF, Shigesada K, Murakami Y, Ito YA . WW domain-containing yes-associated protein (YAP) is a novel transcriptional co-activator. EMBO J 1999; 18: 2551–2562.

    Article  CAS  Google Scholar 

  22. Zanconato F, Forcato M, Battilana G, Azzolin L, Quaranta E, Bodega B et al. Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth. Nat Cell Biol 2015; 17: 1218–1227.

    Article  CAS  Google Scholar 

  23. Yu FX, Zhao B, Guan KL . Hippo pathway in organ size control tissue homeostasis, and cancer. Cell 2015; 163: 811–828.

    Article  CAS  Google Scholar 

  24. Striedinger K, VandenBerg SR, Bala GS, McDermott MW, Gutmann DH, Lal A . The neurofibromatosis 2 tumor suppressor gene product, merlin, regulates human meningioma cell growth by signaling through YAP. Neoplasia 2008; 10: 1204–1212.

    Article  CAS  Google Scholar 

  25. Zhang W, Nandakumar N, Shi Y, Manzano M, Smith A, Graham G et al. Downstream of mutant KRAS, the transcription regulator YAP is essential for neoplastic progression to pancreatic ductal adenocarcinoma. Sci Signal 2014; 7: ra42.

    Article  Google Scholar 

  26. O’Hayre M, Vázquez-Prado J, Kufareva I, Stawiski EW, Handel TM, Seshagiri S et al. The emerging mutational landscape of G proteins and G-protein-coupled receptors in cancer. Nat Rev Cancer 2013; 13: 412–424.

    Article  Google Scholar 

  27. Yu FX, Luo J, Mo JS, Liu G, Kim YC, Meng Z et al. Mutant Gq/11 promote uveal melanoma tumorigenesis by activating YAP. Cancer Cell 2014; 25: 822–830.

    Article  CAS  Google Scholar 

  28. Feng X, Degese MS, Iglesias-Bartolome R, Vaque JP, Molinolo AA, Rodrigues M et al. Hippo-independent activation of YAP by the GNAQ uveal melanoma oncogene through a trio-regulated rho GTPase signaling circuitry. Cancer Cell 2014; 25: 831–845.

    Article  CAS  Google Scholar 

  29. Liu G, Yu FX, Kim YC, Meng Z, Naipauer J, Looney DJ et al. Kaposi sarcoma-associated herpesvirus promotes tumorigenesis by modulating the hippo pathway. Oncogene 2015; 34: 3536–3346.

    Article  CAS  Google Scholar 

  30. Park SA, Kim MJ, Park SY, Kim JS, Lim W, Nam JS et al. TIMP-1 mediates TGF-β-dependent crosstalk between hepatic stellate and cancer cells via FAK signaling. Sci Rep 2015; 5: 16492.

    Article  CAS  Google Scholar 

  31. Eyckmans J, Boudou T, Yu X, Chen CS . A hitchhiker’s guide to mechanobiology. Dev Cell 2011; 21: 35–47.

    Article  CAS  Google Scholar 

  32. 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: 1120–1133.

    Article  CAS  Google Scholar 

  33. Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev 2007; 21: 2747–2761.

    Article  CAS  Google Scholar 

  34. Zhao B, Li L, Tumaneng K, Wang CY, Guan KL . A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCF (beta-TRCP). Genes Dev 2010; 24: 72–85.

    Article  CAS  Google Scholar 

  35. Taniguchi K, Wu LW, Grivennikov SI, de Jong PR, Lian I, Yu FX et al. A gp130-Src-YAP module links inflammation to epithelial regeneration. Nature 2015; 519: 57–62.

    Article  CAS  Google Scholar 

  36. Shanzer M, Adler J, Ricardo-Lax I, Reuven N, Shaul Y . The nonreceptor tyrosine kinase c-Src attenuates SCF(β-TrCP) E3-ligase activity abrogating Taz proteosomal degradation. Proc Natl Acad Sci USA 2017; 114: 1678–1683.

    Article  CAS  Google Scholar 

  37. Plouffe SW, Hong AW, Guan KL . Disease implications of the Hippo/YAP pathway. Trends Mol Med 2015; 21: 212–222.

    Article  CAS  Google Scholar 

  38. Egea V, Zahler S, Rieth N, Neth P, Popp T, Kehe K et al. Tissue inhibitor of metalloproteinase-1 (TIMP-1) regulates mesenchymal stem cells through let-7f microRNA and Wnt/β-catenin signaling. Proc Natl Acad Sci USA 2012; 109: E309–E316.

    Article  CAS  Google Scholar 

  39. Liu XW, Taube ME, Jung KK, Dong Z, Lee YJ, Roshy S et al. Tissue inhibitor of metalloproteinase-1 protects human breast epithelial cells from extrinsic cell death: a potential oncogenic activity of tissue inhibitor of metalloproteinase-1. Cancer Res 2005; 65: 898–906.

    CAS  PubMed  Google Scholar 

  40. Tang Y, Rowe RG, Botvinick EL, Kurup A, Putnam AJ, Seiki M et al. MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis. Dev Cell 2013; 25: 402–416.

    Article  CAS  Google Scholar 

  41. Elbediwy A, Vincent-Mistiaen ZI, Spencer-Dene B, Stone RK, Boeing S, Wculek SK et al. Integrin signaling regulates YAP and TAZ to control skin homeostasis. Development 2016; 143: 1674–1687.

    Article  CAS  Google Scholar 

  42. Martin K, Pritchett J, Llewellyn J, Mullan AF, Athwal VS, Dobie R et al. PAK proteins and YAP-1 signaling downstream of integrin beta-1 in myofibroblasts promote liver fibrosis. Nat Commun 2016; 7: 12502.

    Article  CAS  Google Scholar 

  43. Wang L, Luo JY, Li B, Tian XY, Chen LJ, Huang Y et al. Integrin-YAP/TAZ-JNK cascade mediates atheroprotective effect of unidirectional shear flow. Nature 2016; 540: 579–582.

    Article  CAS  Google Scholar 

  44. Kim NG, Gumbiner BM . Adhesion to fibronectin regulates Hippo signaling via the FAK-Src-PI3K pathway. J Cell Biol 2015; 210: 503–515.

    Article  CAS  Google Scholar 

  45. Plouffe SW, Meng Z, Lin KC, Lin B, Hong AW, Chun JV et al. Characterization of hippo pathway components by gene inactivation. Mol Cell 2016; 64: 993–1008.

    Article  CAS  Google Scholar 

  46. Dupont S, Morsut L, Aragona M, Enzo E, Giulitti S, Cordenonsi M et al. Role of YAP/TAZ in mechanotransduction. Nature 2011; 474: 179–183.

    Article  CAS  Google Scholar 

  47. Fujii M, Toyoda T, Nakanishi H, Yatabe Y, Sato A, Matsudaira Y et al. TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth. J Exp Med 2012; 209: 479–494.

    Article  CAS  Google Scholar 

  48. Aaberg-Jessen C, Christensen K, Offenberg H, Bartels A, Dreehsen T, Hansen S et al. Low expression of tissue inhibitor of metalloproteinases-1 (TIMP-1) in glioblastoma predicts longer patient survival. J Neurooncol 2009; 95: 117–128.

    Article  CAS  Google Scholar 

  49. Honkavuori M, Talvensaari-Mattila A, Puistola U, Turpeenniemi-Hujanen T, Santala M . High serum TIMP-1 is associated with adverse prognosis in endometrial carcinoma. Anticancer Res 2008; 28: 2715–2719.

    PubMed  Google Scholar 

  50. Jackson HW, Defamie V, Waterhouse P, Khokha R . TIMPs: versatile extracellular regulators in cancer. Nat Rev Cancer 2017; 17: 38–53.

    Article  CAS  Google Scholar 

  51. Liu-Chittenden Y, Huang B, Shim JS, Chen Q, Lee SJ, Anders RA et al. Genetic and pharmacological disruption of the TEAD-YAP complex suppresses the oncogenic activity of YAP. Genes Dev 2012; 26: 1300–1305.

    Article  CAS  Google Scholar 

  52. Brodowska K, Al-Moujahed A, Marmalidou A, Meyer Zu Horste M, Cichy J, Miller JW et al. The clinically used photosensitizer Verteporfin (VP) inhibits YAP-TEAD and human retinoblastoma cell growth in vitro without light activation. Exp Eye Res 2014; 124: 67–73.

    Article  CAS  Google Scholar 

  53. Jiao S, Wang H, Shi Z, Dong A, Zhang W, Song X et al. A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer. Cancer Cell 2014; 25: 166–180.

    Article  CAS  Google Scholar 

  54. Mi W, Lin Q, Childress C, Sudol M, Robishaw J, Berlot CH et al. Geranylgeranylation signals to the Hippo pathway for breast cancer cell proliferation and migration. Oncogene 2015; 34: 3095–3106.

    Article  CAS  Google Scholar 

  55. 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: 357–366.

    Article  CAS  Google Scholar 

  56. Zanconato F, Battilana G, Cordenonsi M, Piccolo S . YAP/TAZ as therapeutic targets in cancer. Curr Opin Pharmacol 2016; 29: 26–33.

    Article  CAS  Google Scholar 

  57. Ando T, Kudo Y, Iizuka S, Tsunematsu T, Umehara H, Shrestha M et al. Ameloblastin induces tumor suppressive phenotype and enhances chemosensitivity to doxorubicin via Src-Stat3 inactivation in osteosarcoma. Sci Rep 2017; 7: 40187.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Professor Koichiro Ozawa (Department of Pharmacotherapy, Hiroshima University) for valuable discussion and Professor Makiko Fujii (Department of Global Dental Medicine and Molecular Oncology, Hiroshima University) for providing us HA-tagged YAP-WT vector and anti-HA antibody. This work was funded, in part, by JSPS KAKENHI Grant Number JP25293373 and JP16H05503 to (TT) and 17K17084 to (TA). Hanako Umehara currently belongs to department of advanced prosthodontics, Hiroshima University.

Author information

Authors and Affiliations

  1. Department of Oral and Maxillofacial Pathobiology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

    T Ando, D Charindra, M Shrestha, H Umehara, M Miyauchi & T Takata

  2. Center of Oral Clinical Examination, Hiroshima University Hospital, Hiroshima, Japan

    I Ogawa

Authors
  1. T Ando
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D Charindra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Shrestha
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H Umehara
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. I Ogawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M Miyauchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Takata
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Takata.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies this paper on the Oncogene website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ando, T., Charindra, D., Shrestha, M. et al. Tissue inhibitor of metalloproteinase-1 promotes cell proliferation through YAP/TAZ activation in cancer. Oncogene 37, 263–270 (2018). https://doi.org/10.1038/onc.2017.321

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2017.321

This article is cited by

Search

Advanced search

Quick links