The Hippo transducer TAZ promotes epithelial to mesenchymal transition and cancer stem cell maintenance in oral cancer

Abstract

The Hippo pathway has emerged as a fundamental regulator in tissue growth, organ size and stem cell functions, and tumorigenesis when deregulated. However, its roles and associated molecular mechanisms underlying oral squamous cell carcinoma (OSCC) initiation and progression remain largely unknown. Here, we identified TAZ, the downstream effector of Hippo signaling, as a novel bona fide oncogene by promoting cell proliferation, migration/invasion and chemoresistance in OSCC. TAZ promoted epithelial-to-mesenchymal transition (EMT) and also was involved in TGF-β1-induced EMT in oral cancer cells. Furthermore, enriched TAZ sustained self-renewal, maintenance, tumor-seeding potential of oral cancer stem cells (CSCs). Remarkably, enforced TAZ overexpression conferred CSCs-like properties on differentiated non-CSCs and fueled phenotypic transition from non-CSCs to CSCs-like cells. Mechanistically, TAZ-TEADs binding and subsequent transcriptional activation of EMT mediators and pluripotency factors are presumably responsible for TAZ-mediated EMT and non-CSCs-to-CSCs conversion. Importantly, aberrant TAZ overexpression was found to be associated with tumor size, pathological grade and cervical lymph node metastasis, as well as unfavorable prognosis. Pharmacological repression of TAZ by simvastatin resulted in potent anti-cancer effects against OSCC. Taken together, our findings have revealed critical links between TAZ, EMT and CSCs in OSCC initiation and progression, and also established TAZ as a novel cancer biomarker and viable druggable target for OSCC therapeutics.

Molecular Pathways: Hippo Signaling, a Critical Tumor Suppressor

“…In neuroblastoma cell lines, studies have shown how TAZ upregulates connective tissue growth factor (CTGF) known to induce EMT (19). Moreover, in oral cancer cells, TAZ has also been found to be involved in TGF-β1 induced EMT (20). …”

“…Interestingly, the SREBP/mevalonate cascade is needed to activate RhoGTPase. As this metabolic pathway is inhibited by statins, simvastatin has also been reported to repress TAZ, leading to potent anti-cancer effects (20, 59). …”

Overexpression of lncRNA WWTR1‐AS1 associates with tumor aggressiveness and unfavorable survival in head‐neck squamous cell carcinoma

“…Dysregulation of Hippo pathway and hyperactivation of WWTR1 and YAP1 essentially have been proved in promoting cancer outgrowth, locoregional recurrence and metastatic spreading . Notably, mounting evidence support that WWTR1 as a putative oncogene was commonly overexpressed in multiple cancers such as breast cancer, lung cancer, papillary thyroid carcinoma, and HNSCC . Given the facts that WWTR1‐AS1 is a NAT corresponding to the 5′‐UTR of WWTR1, we addressed the hypothesis that WWTR1‐AS1 modulated cell phenotypes by regulating WWTR1 in HNSCC by experimental and bioinformatics approaches.…”

The 2016 John J. Abel Award Lecture: Targeting the Mechanical Microenvironment in Cancer

“…A key enzyme in this pathway is 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, which is inhibited by statins. Statin treatment caused cytoplasmic relocalization and inhibition of YAP/TAZ in several cancer types and a reduction of cancer stem cell growth and tumor xenografts (Sorrentino et al, 2014;Wang et al, 2014;Li et al, 2015). Bisphosphonates and geranylgeranyl transferase 1 inhibitors also target the mevalonate pathways and have similar effects on inhibiting YAP and TAZ (Sorrentino et al, 2014;Mi et al, 2015).…”

“…Low toxicity in phase 1 trials, some disease stabilization YAP/TAZ inhibition and cytoplasmic relocalization; reduction in cancer stem cell growth and tumor xenograft models Sorrentino et al, 2014;Wang et al, 2014;Li et al, 2015 Verteporfin YAP/TAZ inhibitor Inhibits YAP-TEAD binding and suppresses downstream signaling in retinoblastoma Liu-Chittenden et al, 2012;Brodowska et al, 2014;Wang et al, 2015 Dasatinib Src inhibitor Monotherapy phase 2 trials show some effect in breast and prostate cancer and melanoma, and no benefit in other cancer types such as small cell lung cancer; combination in with statin treatment has a greater effect on downstream YAP/TAZ activity Mayer and Krop, 2010;Miller et al, 2010;Rosenbluh et al, 2012;Calvo et al, 2013;Taccioli et al, 2015 HMG-CoA, 3-hydroxy-3-methyl-glutaryl-coenzyme A; GIST, gatrointestinal stromal tumor.…”