title: 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.
authors.affiliation: Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China; Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Zhongwu
authors.initials: Z
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China; Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China; Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Chunping
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Dongmiao
authors.initials: D
authors.lastname: Wang
authors.affiliation: Department of Oral Pathology, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Oral Pathology, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Qi
authors.affiliation: Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Qiu
authors.affiliation: Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Jinhai
authors.initials: J
authors.lastname: Ye
authors.affiliation: Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Heming
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Hongbing
authors.initials: H
authors.lastname: Jiang
authors.affiliation: Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China; Department of Oral Pathology, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China.
authors.forename: Laikui
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Head & Neck Oncology, Jiangsu Cancer Hospital, Jiangsu 210000, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, NY 10032, USA.
authors.forename: Liang-Nian
authors.initials: LN
authors.lastname: Song
authors.affiliation: Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China; Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China. Electronic address: cj992118@yahoo.com.
authors.forename: Jianrong
authors.initials: J
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China; Department of Oral and Maxillofacial Surgery, Affiliated Hospital of Stomatology, Nanjing Medical University, Jiangsu 210029, China. Electronic address: leonardo_cheng@163.com.
authors.forename: Jie
authors.initials: J
authors.lastname: Cheng
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D000090683:Hippo Signaling Pathway; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins
chemical_list: D014408:Biomarkers, Tumor; D047908:Intracellular Signaling Peptides and Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000091364:Transcriptional Coactivator with PDZ-Binding Motif Proteins; C551991:WWTR1 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: Cancer stem cell; Epithelial to mesenchymal transition; Hippo; Oral squamous cell carcinoma; TAZ