The Hippo effector TAZ (WWTR1) transforms myoblasts and TAZ abundance is associated with reduced survival in embryonal rhabdomyosarcoma

Abdalla Mohamed, Congshan Sun, Vanessa De Mello, Joanna Selfe, Edoardo Missiaglia, Janet Shipley, Graeme I. Murray, Pete S. Zammit, Henning Wackerhage

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Abstract

The Hippo effector YAP has recently been identified as a potent driver of embryonal rhabdomyosarcoma (ERMS). Most reports suggest that the YAP paralogue TAZ (gene symbol WWTR1) functions as YAP but, in skeletal muscle, TAZ has been reported to promote myogenic differentiation, whereas YAP inhibits it. Here, we investigated whether TAZ is also a rhabdomyosarcoma oncogene or whether TAZ acts as a YAP antagonist. Immunostaining of rhabdomyosarcoma tissue microarrays revealed that TAZ is significantly associated with poor survival in ERMS. In 12% of fusion gene-negative rhabdomyosarcomas, the TAZ locus is gained, which is correlated with increased expression. Constitutively active TAZ S89A significantly increased proliferation of C2C12 myoblasts and, importantly, colony formation on soft agar, suggesting transformation. However, TAZ then switches to enhance myogenic differentiation in C2C12 myoblasts, unlike YAP. Conversely, lentiviral shRNA-mediated TAZ knockdown in human ERMS cells reduced proliferation and anchorage-independent growth. While TAZ S89A or YAP1 S127A similarly activated the 8XGTIIC–Luc Hippo reporter, only YAP1 S127A activated the Brachyury (T-box) reporter. Consistent with its oncogene function, TAZ S89A induced expression of the ERMS cancer stem cell gene Myf5 and the serine biosynthesis pathway (Phgdh, Psat1, Psph) in C2C12 myoblasts. Thus, TAZ is associated with poor survival in ERMS and could act as an oncogene in rhabdomyosarcoma. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Original languageEnglish
Pages (from-to)3-14
Number of pages12
JournalThe Journal of pathology
Volume240
Issue number1
Early online date22 Aug 2016
DOIs
Publication statusPublished - Sep 2016

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Embryonal Rhabdomyosarcoma
Myoblasts
Rhabdomyosarcoma
Oncogenes
Survival
Neoplastic Stem Cells
Germ Cell and Embryonal Neoplasms
Gene Fusion
Ireland
Serine
Small Interfering RNA
Genes
Agar
Skeletal Muscle
Cell Proliferation
Pathology
Growth

Keywords

  • hippo pathway
  • TAZ
  • WWTR1
  • embryonal rhabdomyosarcoma
  • myoblasts

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The Hippo effector TAZ (WWTR1) transforms myoblasts and TAZ abundance is associated with reduced survival in embryonal rhabdomyosarcoma. / Mohamed, Abdalla; Sun, Congshan; De Mello, Vanessa; Selfe, Joanna; Missiaglia, Edoardo; Shipley, Janet; Murray, Graeme I.; Zammit, Pete S.; Wackerhage, Henning.

In: The Journal of pathology, Vol. 240, No. 1, 09.2016, p. 3-14.

Research output: Contribution to journalArticle

Mohamed, A, Sun, C, De Mello, V, Selfe, J, Missiaglia, E, Shipley, J, Murray, GI, Zammit, PS & Wackerhage, H 2016, 'The Hippo effector TAZ (WWTR1) transforms myoblasts and TAZ abundance is associated with reduced survival in embryonal rhabdomyosarcoma', The Journal of pathology, vol. 240, no. 1, pp. 3-14. https://doi.org/10.1002/path.4745
Mohamed, Abdalla ; Sun, Congshan ; De Mello, Vanessa ; Selfe, Joanna ; Missiaglia, Edoardo ; Shipley, Janet ; Murray, Graeme I. ; Zammit, Pete S. ; Wackerhage, Henning. / The Hippo effector TAZ (WWTR1) transforms myoblasts and TAZ abundance is associated with reduced survival in embryonal rhabdomyosarcoma. In: The Journal of pathology. 2016 ; Vol. 240, No. 1. pp. 3-14.
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abstract = "The Hippo effector YAP has recently been identified as a potent driver of embryonal rhabdomyosarcoma (ERMS). Most reports suggest that the YAP paralogue TAZ (gene symbol WWTR1) functions as YAP but, in skeletal muscle, TAZ has been reported to promote myogenic differentiation, whereas YAP inhibits it. Here, we investigated whether TAZ is also a rhabdomyosarcoma oncogene or whether TAZ acts as a YAP antagonist. Immunostaining of rhabdomyosarcoma tissue microarrays revealed that TAZ is significantly associated with poor survival in ERMS. In 12{\%} of fusion gene-negative rhabdomyosarcomas, the TAZ locus is gained, which is correlated with increased expression. Constitutively active TAZ S89A significantly increased proliferation of C2C12 myoblasts and, importantly, colony formation on soft agar, suggesting transformation. However, TAZ then switches to enhance myogenic differentiation in C2C12 myoblasts, unlike YAP. Conversely, lentiviral shRNA-mediated TAZ knockdown in human ERMS cells reduced proliferation and anchorage-independent growth. While TAZ S89A or YAP1 S127A similarly activated the 8XGTIIC–Luc Hippo reporter, only YAP1 S127A activated the Brachyury (T-box) reporter. Consistent with its oncogene function, TAZ S89A induced expression of the ERMS cancer stem cell gene Myf5 and the serine biosynthesis pathway (Phgdh, Psat1, Psph) in C2C12 myoblasts. Thus, TAZ is associated with poor survival in ERMS and could act as an oncogene in rhabdomyosarcoma. {\circledC} 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.",
keywords = "hippo pathway, TAZ, WWTR1, embryonal rhabdomyosarcoma, myoblasts",
author = "Abdalla Mohamed and Congshan Sun and {De Mello}, Vanessa and Joanna Selfe and Edoardo Missiaglia and Janet Shipley and Murray, {Graeme I.} and Zammit, {Pete S.} and Henning Wackerhage",
note = "Acknowledgements This study was funded by Sarcoma UK, Friends of Anchor and the Medical Research Council grant number 99477 awarded to HW and PSZ. This work was also supported, in part, by NHS funding to the NIHR Biomedical Research Centre at the Royal Marsden Hospital and the Institute of Cancer Research, and the Chris Lucas Trust, UK. We also thank the CCLG (Children's cancer and leukaemia group) Tissue Bank for access to samples, and contributing CCLG centres, including members of the ECMC paediatric network. The CCLG Tissue Bank is funded by Cancer Research UK and CCLG. The Zammit lab is also currently supported by Muscular Dystrophy UK (RA3-3052), Association Fran{\cc}aise Contre les Myopathies (17865, 20082, 19105 and 16050) and the FSH (Fascioscapulohumeral muscular dystrophy) Society (Shack Family and Friends research grant (FSHS-82013-06)). In addition, we would like to thank Prof Kun-Liang Guan and Prof Malcolm Logan for kindly providing constructs.",
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T1 - The Hippo effector TAZ (WWTR1) transforms myoblasts and TAZ abundance is associated with reduced survival in embryonal rhabdomyosarcoma

AU - Mohamed, Abdalla

AU - Sun, Congshan

AU - De Mello, Vanessa

AU - Selfe, Joanna

AU - Missiaglia, Edoardo

AU - Shipley, Janet

AU - Murray, Graeme I.

AU - Zammit, Pete S.

AU - Wackerhage, Henning

N1 - Acknowledgements This study was funded by Sarcoma UK, Friends of Anchor and the Medical Research Council grant number 99477 awarded to HW and PSZ. This work was also supported, in part, by NHS funding to the NIHR Biomedical Research Centre at the Royal Marsden Hospital and the Institute of Cancer Research, and the Chris Lucas Trust, UK. We also thank the CCLG (Children's cancer and leukaemia group) Tissue Bank for access to samples, and contributing CCLG centres, including members of the ECMC paediatric network. The CCLG Tissue Bank is funded by Cancer Research UK and CCLG. The Zammit lab is also currently supported by Muscular Dystrophy UK (RA3-3052), Association Française Contre les Myopathies (17865, 20082, 19105 and 16050) and the FSH (Fascioscapulohumeral muscular dystrophy) Society (Shack Family and Friends research grant (FSHS-82013-06)). In addition, we would like to thank Prof Kun-Liang Guan and Prof Malcolm Logan for kindly providing constructs.

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N2 - The Hippo effector YAP has recently been identified as a potent driver of embryonal rhabdomyosarcoma (ERMS). Most reports suggest that the YAP paralogue TAZ (gene symbol WWTR1) functions as YAP but, in skeletal muscle, TAZ has been reported to promote myogenic differentiation, whereas YAP inhibits it. Here, we investigated whether TAZ is also a rhabdomyosarcoma oncogene or whether TAZ acts as a YAP antagonist. Immunostaining of rhabdomyosarcoma tissue microarrays revealed that TAZ is significantly associated with poor survival in ERMS. In 12% of fusion gene-negative rhabdomyosarcomas, the TAZ locus is gained, which is correlated with increased expression. Constitutively active TAZ S89A significantly increased proliferation of C2C12 myoblasts and, importantly, colony formation on soft agar, suggesting transformation. However, TAZ then switches to enhance myogenic differentiation in C2C12 myoblasts, unlike YAP. Conversely, lentiviral shRNA-mediated TAZ knockdown in human ERMS cells reduced proliferation and anchorage-independent growth. While TAZ S89A or YAP1 S127A similarly activated the 8XGTIIC–Luc Hippo reporter, only YAP1 S127A activated the Brachyury (T-box) reporter. Consistent with its oncogene function, TAZ S89A induced expression of the ERMS cancer stem cell gene Myf5 and the serine biosynthesis pathway (Phgdh, Psat1, Psph) in C2C12 myoblasts. Thus, TAZ is associated with poor survival in ERMS and could act as an oncogene in rhabdomyosarcoma. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

AB - The Hippo effector YAP has recently been identified as a potent driver of embryonal rhabdomyosarcoma (ERMS). Most reports suggest that the YAP paralogue TAZ (gene symbol WWTR1) functions as YAP but, in skeletal muscle, TAZ has been reported to promote myogenic differentiation, whereas YAP inhibits it. Here, we investigated whether TAZ is also a rhabdomyosarcoma oncogene or whether TAZ acts as a YAP antagonist. Immunostaining of rhabdomyosarcoma tissue microarrays revealed that TAZ is significantly associated with poor survival in ERMS. In 12% of fusion gene-negative rhabdomyosarcomas, the TAZ locus is gained, which is correlated with increased expression. Constitutively active TAZ S89A significantly increased proliferation of C2C12 myoblasts and, importantly, colony formation on soft agar, suggesting transformation. However, TAZ then switches to enhance myogenic differentiation in C2C12 myoblasts, unlike YAP. Conversely, lentiviral shRNA-mediated TAZ knockdown in human ERMS cells reduced proliferation and anchorage-independent growth. While TAZ S89A or YAP1 S127A similarly activated the 8XGTIIC–Luc Hippo reporter, only YAP1 S127A activated the Brachyury (T-box) reporter. Consistent with its oncogene function, TAZ S89A induced expression of the ERMS cancer stem cell gene Myf5 and the serine biosynthesis pathway (Phgdh, Psat1, Psph) in C2C12 myoblasts. Thus, TAZ is associated with poor survival in ERMS and could act as an oncogene in rhabdomyosarcoma. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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