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TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation

Oncogene volume 38, pages 1966–1978 (2019)Cite this article

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Abstract

Malignant mesothelioma (MM) constitutes a very aggressive tumor that is caused by asbestos exposure after long latency. The NF2 tumor suppressor gene is mutated in 40–50% of MM; moreover, one of its downstream signaling cascades, the Hippo signaling pathway, is also frequently inactivated in MM cells. Although the YAP transcriptional coactivator, which is regulated by the Hippo pathway, can function as a pro-oncogenic protein, the role of TAZ, a paralog of YAP, in MM cells has not yet been clarified. Here, we show that TAZ is expressed and underphosphorylated (activated) in the majority of MM cells compared to immortalized mesothelial cells. ShRNA-mediated TAZ knockdown highly suppressed cell proliferation, anchorage-independent growth, cell motility, and invasion in MM cells harboring activated TAZ. Conversely, transduction of an activated form of TAZ in immortalized mesothelial cells enhanced these in vitro phenotypes and conferred tumorigenicity in vivo. Microarray analysis determined that activated TAZ most significantly enhanced the transcription of genes related to “cytokine-cytokine receptor interaction.” Among selected cytokines, we found that IL-1 signaling activation plays a major role in proliferation in TAZ-activated MM cells. Both IL1B knockdown and an IL-1 receptor antagonist significantly suppressed malignant phenotypes of immortalized mesothelial cells and MM cells with activated TAZ. Overall, these results indicate an oncogenic role for TAZ in MMs via transcriptional induction of distinct pro-oncogenic genes including cytokines. Among these, IL-1 signaling appears as one of the most important cascades, thus potentially serving as a target pathway in MM cells harboring Hippo pathway inactivation.

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References

  1. Yap TA, Aerts JG, Popat S, Fennell DA. Novel insights into mesothelioma biology and implications for therapy. Nat Rev Cancer. 2017;17:475–88.

    Article  CAS  Google Scholar 

  2. Frank AL, Joshi TK. The global spread of asbestos. Ann Glob Health. 2014;80:257–62.

    Article  Google Scholar 

  3. Robinson BW, Lake RA. Advances in malignant mesothelioma. N Engl J Med. 2005;353:1591–603.

    Article  CAS  Google Scholar 

  4. Disselhorst MMJ, Burgers SJA, Baas P. Optimal therapy of advanced stage mesothelioma. Curr Treat Options Oncol. 2017;18:48.

    Article  Google Scholar 

  5. Bibby AC, Tsim S, Kanellakis N, Ball H, Talbot DC, Blyth KG, et al. Malignant pleural mesothelioma: an update on investigation, diagnosis and treatment. Eur Respir Rev.. 2016;25:472–86.

    Article  Google Scholar 

  6. Nelson DB, Rice DC, Niu J, Atay S, Vaporciyan AA, Antonoff M, et al. Long-term survival outcomes of cancer-directed surgery for malignant pleural mesothelioma: propensity score matching analysis. J Clin Oncol. 2017;35:3354–62.

    Article  Google Scholar 

  7. Bianchi AB, Mitsunaga SI, Cheng JQ, Klein WM, Jhanwar SC, Seizinger B, et al. High frequency of inactivating mutations in the neurofibromatosis type 2 gene (NF2) in primary malignant mesotheliomas. Proc Natl Acad Sci USA. 1995;92:10854–8.

    Article  CAS  Google Scholar 

  8. Bueno R, Stawiski EW, Goldstein LD, Durinck S, De Rienzo A, Modrusan Z, et al. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat Genet. 2016;48:407–16.

    Article  CAS  Google Scholar 

  9. Sekido Y, Pass HI, Bader S, Mew DJ, Christman MF, Gazdar AF, et al. Neurofibromatosis type 2 (NF2) gene is somatically mutated in mesothelioma but not in lung cancer. Cancer Res. 1995;55:1227–31.

    CAS  PubMed  Google Scholar 

  10. Felley-Bosco E, Stahel R. Hippo/YAP pathway for targeted therapy. Transl Lung Cancer Res. 2014;3:75–83.

    CAS  PubMed  Google Scholar 

  11. Sekido Y. Molecular pathogenesis of malignant mesothelioma. Carcinogenesis. 2013;34:1413–9.

    Article  CAS  Google Scholar 

  12. Yu FX, Zhao B, Guan KL. Hippo pathway in organ size control, tissue homeostasis, and cancer. Cell. 2015;163:811–28.

    Article  CAS  Google Scholar 

  13. Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13:246–57.

    Article  CAS  Google Scholar 

  14. Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, et al. LATS2 is a tumor suppressor gene of malignant mesothelioma. Cancer Res. 2011;71:873–83.

    Article  CAS  Google Scholar 

  15. Tanaka I, Osada H, Fujii M, Fukatsu A, Hida T, Horio Y, et al. LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade. Oncogene. 2015;34:73–83.

    Article  CAS  Google Scholar 

  16. Tranchant R, Quetel L, Tallet A, Meiller C, Renier A, de Koning L, et al. Co-occurring mutations of tumor suppressor genes, LATS2 and NF2, in malignant pleural mesothelioma. Clin Cancer Res. 2017;23:3191–202.

    Article  CAS  Google Scholar 

  17. Yokoyama T, Osada H, Murakami H, Tatematsu Y, Taniguchi T, Kondo Y, et al. YAP1 is involved in mesothelioma development and negatively regulated by Merlin through phosphorylation. Carcinogenesis. 2008;29:2139–46.

    Article  CAS  Google Scholar 

  18. Fujii M, Toyoda T, Nakanishi H, Yatabe Y, Sato A, Matsudaira Y, et al. TGF-beta synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth. J Exp Med. 2012;209:479–94.

    Article  CAS  Google Scholar 

  19. Mizuno T, Murakami H, Fujii M, Ishiguro F, Tanaka I, Kondo Y, et al. YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle-promoting genes. Oncogene. 2012;31:5117–22.

    Article  CAS  Google Scholar 

  20. Kakiuchi T, Takahara T, Kasugai Y, Arita K, Yoshida N, Karube K, et al. Modeling mesothelioma utilizing human mesothelial cells reveals involvement of phospholipase-C beta 4 in YAP-active mesothelioma cell proliferation. Carcinogenesis. 2016;37:1098–109.

    Article  CAS  Google Scholar 

  21. Hansen CG, Moroishi T, Guan KL. YAP and TAZ: a nexus for Hippo signaling and beyond. Trends Cell Biol. 2015;25:499–513.

    Article  CAS  Google Scholar 

  22. Huang W, Lv X, Liu C, Zha Z, Zhang H, Jiang Y, et al. The N-terminal phosphodegron targets TAZ/WWTR1 protein for SCFbeta-TrCP-dependent degradation in response to phosphatidylinositol 3-kinase inhibition. J Biol Chem. 2012;287:26245–53.

    Article  CAS  Google Scholar 

  23. Tian Y, Kolb R, Hong JH, Carroll J, Li D, You J, et al. TAZ promotes PC2 degradation through a SCFbeta-Trcp E3 ligase complex. Mol Cell Biol. 2007;27:6383–95.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. 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 

  26. Kanehisa M, Goto S, Hattori M, Aoki-Kinoshita KF, Itoh M, Kawashima S, et al. From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res. 2006;34:D354–357.

    Article  CAS  Google Scholar 

  27. Adachi Y, Aoki C, Yoshio-Hoshino N, Takayama K, Curiel DT, Nishimoto N. Interleukin-6 induces both cell growth and VEGF production in malignant mesotheliomas. Int J Cancer. 2006;119:1303–11.

    Article  CAS  Google Scholar 

  28. Kadariya Y, Menges CW, Talarchek J, Cai KQ, Klein-Szanto AJ, Pietrofesa RA, et al. Inflammation-related IL1beta/IL1R signaling promotes the development of asbestos-induced malignant mesothelioma. Cancer Prev Res (Phila). 2016;9:406–14.

    Article  CAS  Google Scholar 

  29. Stadlmann S, Pollheimer J, Renner K, Zeimet AG, Offner FA, Amberger A. Response of human peritoneal mesothelial cells to inflammatory injury is regulated by interleukin-1beta and tumor necrosis factor-alpha. Wound Repair Regen. 2006;14:187–94.

    Article  Google Scholar 

  30. Wang Y, Faux SP, Hallden G, Kirn DH, Houghton CE, Lemoine NR, et al. Interleukin-1beta and tumour necrosis factor-alpha promote the transformation of human immortalised mesothelial cells by erionite. Int J Oncol. 2004;25:173–8.

    CAS  PubMed  Google Scholar 

  31. Menezes ME, Bhatia S, Bhoopathi P, Das SK, Emdad L, Dasgupta S, et al. MDA-7/IL-24: multifunctional cancer killing cytokine. Adv Exp Med Biol. 2014;818:127–53.

    Article  CAS  Google Scholar 

  32. Whitaker EL, Filippov VA, Duerksen-Hughes PJ. Interleukin 24: mechanisms and therapeutic potential of an anti-cancer gene. Cytokine Growth Factor Rev. 2012;23:323–31.

    Article  CAS  Google Scholar 

  33. Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, et al. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science. 2005;309:1074–8.

    Article  CAS  Google Scholar 

  34. Chan SW, Lim CJ, Loo LS, Chong YF, Huang C, Hong W. TEADs mediate nuclear retention of TAZ to promote oncogenic transformation. J Biol Chem. 2009;284:14347–58.

    Article  CAS  Google Scholar 

  35. Mahoney WM Jr., Hong JH, Yaffe MB, Farrance IK. The transcriptional co-activator TAZ interacts differentially with transcriptional enhancer factor-1 (TEF-1) family members. Biochem J. 2005;388:217–25.

    Article  CAS  Google Scholar 

  36. Varelas X, Sakuma R, Samavarchi-Tehrani P, Peerani R, Rao BM, Dembowy J, et al. TAZ controls Smad nucleocytoplasmic shuttling and regulates human embryonic stem-cell self-renewal. Nat Cell Biol. 2008;10:837–48.

    Article  CAS  Google Scholar 

  37. Chan SW, Lim CJ, Guo K, Ng CP, Lee I, Hunziker W, et al. A role for TAZ in migration, invasion, and tumorigenesis of breast cancer cells. Cancer Res. 2008;68:2592–8.

    Article  CAS  Google Scholar 

  38. Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C, et al. The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell. 2011;147:759–72.

    Article  CAS  Google Scholar 

  39. Bhat KP, Salazar KL, Balasubramaniyan V, Wani K, Heathcock L, Hollingsworth F, et al. The transcriptional coactivator TAZ regulates mesenchymal differentiation in malignant glioma. Genes Dev. 2011;25:2594–609.

    Article  CAS  Google Scholar 

  40. Yang Z, Nakagawa K, Sarkar A, Maruyama J, Iwasa H, Bao Y, et al. Screening with a novel cell-based assay for TAZ activators identifies a compound that enhances myogenesis in C2C12 cells and facilitates muscle repair in a muscle injury model. Mol Cell Biol. 2014;34:1607–21.

    Article  Google Scholar 

  41. 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.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Ms. Ikue Hasegawa, Miwako Nishizawa, and Haruna Ikeda for technical assistance. We thank Dr. Hata for TAZ expression lentiviruses and Dr. Gazdar for MM cell lines. This work was supported by JSPS KAKENHI 25090053 (YS), 16H04706 (YS), and 17K19628 (YS); AMED P-PRIME and P-CREATE (YS); Aichi Cancer Research Foundation (TS); and Takeda Science Foundation (TS).

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Authors and Affiliations

  1. Division of Cancer Biology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, Japan

    Akihiro Matsushita, Tatsuhiro Sato, Satomi Mukai, Maho Okuda & Yoshitaka Sekido

  2. Department of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan

    Akihiro Matsushita & Yoshinori Hasegawa

  3. Division of Pathophysiology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, Japan

    Teruaki Fujishita, Emi Mishiro-Sato & Masahiro Aoki

  4. Field of Cancer Pathobiology and Informatics, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya, Aichi, Japan

    Masahiro Aoki & Yoshitaka Sekido

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  1. Akihiro Matsushita
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Correspondence to Yoshitaka Sekido.

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Matsushita, A., Sato, T., Mukai, S. et al. TAZ activation by Hippo pathway dysregulation induces cytokine gene expression and promotes mesothelial cell transformation. Oncogene 38, 1966–1978 (2019). https://doi.org/10.1038/s41388-018-0417-7

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