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

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.

YAP and the Hippo pathway in pediatric cancer

“…In pathologic conditions, phosphorylation of TAZ leads to its cytoplasmic retention and delays myogenic differentiation. 23 Similarly, YAP is retained in the nucleus, where it promotes satellite cells proliferation, and prevents their differentiation. Rhabdomyosarcomas are tumors of skeletal muscle origin that exhibit overexpression of the myogenic regulatory proteins, MYOD1 and myogenin.…”

“…26 Additional data have also suggested that TAZ may play a role, albeit less prominent than that of YAP, in the pathogenesis of aRMS. 23 YAP overexpression is also implicated as a key factor in the development of embryonal rhabdomyosarcoma (eRMS). A recent study using multiple genetically engineered mice has demonstrated that YAP protein overexpression transforms activated satellite cells leading to the development of embryonal rhabdomyosarcoma-like tumors.…”

“…Knockdown of TAZ in human eRMS cell lines reduces their proliferation and anchorage-independent growth. 23 Expression of YAP and TAZ in clinical cases of rhabdomyosarcoma signifies their potential applications as diagnostic and prognostic biomarkers. Both proteins show slightly more expression in eRMS than in aRMS.…”

“…In immunohistochemical experiments of tissue microarray samples, YAP and TAZ are detected in 87% and 55% of eRMS and in 72% and 36% of aRMS respectively. 23,26 Activity of both proteins is related to poor patient prognosis and adverse clinical outcome. In eRMS, YAP protein expression correlates with advanced clinical stage and its gene expression correlates with reduced survival.…”

“…26 TAZ expression is also associated with short survival in eRMS. 23 In this aspect, blocking or modulating YAP or TAZ activity may be considered as potential therapy for rhabdomyosarcoma. 27 Ewing's sarcoma Sarcomas in general are hypothesized to develop from mesenchymal stem/progenitor cells, which are able to differentiate into many cell types and give rise to several adult human tumors.…”