Hippo/YAP Signaling Pathway: A Promising Therapeutic Target in Bone Paediatric Cancers?

Abstract

Osteosarcoma and Ewing sarcoma are the most prevalent bone pediatric tumors. Despite intensive basic and medical research studies to discover new therapeutics and to improve current treatments, almost 40% of osteosarcoma and Ewing sarcoma patients succumb to the disease. Patients with poor prognosis are related to either the presence of metastases at diagnosis or resistance to chemotherapy. Over the past ten years, considerable interest for the Hippo/YAP signaling pathway has taken place within the cancer research community. This signaling pathway operates at different steps of tumor progression: Primary tumor growth, angiogenesis, epithelial to mesenchymal transition, and metastatic dissemination. This review discusses the current knowledge about the involvement of the Hippo signaling pathway in cancer and specifically in paediatric bone sarcoma progression.

Keywords: Ewing sarcoma; YAP; hippo signaling pathway; osteosarcoma.

Figure 1

The Hippo/yes-associated protein (YAP) signaling pathway in mammals. When the Hippo signaling pathway is active, MST1/2 protein kinases (mammalian STE20-like kinase 1/2) are phosphorylated by NF2 (neurofibromatosis type 2), KIBRA, or TAO1-3. MST1/2 activates LATS1/2 (large tumor suppressor 1/2) proteins which are also stimulated by Sav1 (salvador) and Rassf (ras association domain family) proteins. LATS1/2 then phosphorylates YAP protein which is retained in the cytoplasm or is degraded by the proteasome. MOB1 (monopolar spindle-one-binder) and AMOT (angiomantin) proteins favor LATS1/2 phosphorylation and activity. When the Hippo signaling pathway is inactive, YAP is not phosphorylated and translocates to the nucleus where it can exert its transcriptional activity by binding to TEAD (transcriptional enhanced associate domain). YAP thus regulates the expression of specific targets such as CTGF (connective tissue growth factor), BIRC5 (baculoviral inhibitor of apoptosis repeat-containing 5), or Cyr61 (cysteine-rich angiogenic inducer 61).

Figure 2

Successive steps in paediatric bone tumour progression. Hypothetical implication of the YAP signaling pathway. YAP (yes-associated transcription factor coactivator) plays a major role at various crucial steps during tumor progression. In pediatric bone tumors, the Hippo signaling pathway may be involved in primary tumor growth, tumor angiogenesis, epithelial-mesenchymal transition, intravasation, extravasation, cell survival, and metastatic dissemination.

Figure 3

Crosstalk between YAP signaling pathway and both TEAD and TGF-β pathways. When the Hippo signaling pathway is inactive, MST1/2 (mammalian STE20-like kinase 1/2) activates LATS1/2 (large tumor suppressor 1/2) proteins. LATS1/2 then phosphorylates YAP (yes-associated protein) which is retained in the cytoplasm or is degraded by the proteasome. When the Hippo signaling pathway is inactive, YAP is not phosphorylated and translocates to the nucleus where it can exert its transcriptional activity by binding to TEAD (transcriptional enhanced associate domain). YAP regulates the expression of specific targets involved in the cellular proliferation and thus in the primary tumor growth.

Figure 4

YAP drug targets. Verteporfin blocks YAP (yes-associated protein) signaling pathway either by decreasing YAP expression or by inhibiting YAP–TEAD (transcriptional enhanced associate domain) interactions. Dasatinid decreases LATS1/2 (large tumor suppressor 1/2) phosphorylation and activity driven by Src activity. JQ1 blocks YAP driven BRD4 (bromodomain-containing protein 4) activity by inhibiting BRD4 association to chromatin (Ac: Acetylations).