title: WSTF promotes proliferation and invasion of lung cancer cells by inducing EMT via PI3K/Akt and IL-6/STAT3 signaling pathways.
abstract: Williams syndrome transcription factor (WSTF), which is encoded by the BAZ1B gene, was first identified as a hemizygously deleted gene in patients with Williams syndrome. WSTF protein has been reported to be involved in transcription, replication, chromatin remodeling and DNA damage response, and also functions as a tyrosine protein kinase. However, the function of WSTF in cancer is not known. Here, we show that WSTF overexpression promotes proliferation, colony formation, migration and invasion of lung cancer A549 and H1299 cells. WSTF overexpression also promotes tumor growth and invasive abilities of lung cancer cells in mouse xenograft models. cDNA microarray and subsequent qRT-PCR validation revealed that WSTF overexpression significantly upregulated the expression of EMT (epithelial to mesenchymal transition) marker fibronectin (FN1) and EMT-inducing genes Fos and CEACAM6. The changes of EMT markers including downregulated E-cadherin and upregulated N-cadherin and FN1 were further confirmed at both mRNA and protein levels upon WSTF overexpression, with typical morphological changes of EMT. Furthermore, WSTF activates both PI3K/Akt and IL-6/STAT3 oncogenic signaling pathways. Treatment with PI3K inhibitor ZSTK474 or STAT3 inhibitor niclosamide reversed the effects of WSTF overexpression by inhibiting cell proliferation, migration and invasion, with decreased level of p-Akt, p-STAT3 and IL-6. ZSTK474 and niclosamide also reversed EMT markers and EMT-inducing proteins including Snail, Slug, Twist and CEACAM6 in WSTF-overexpressing A549 cells. Taken together, these results demonstrate that WSTF may act as an oncoprotein in lung cancer to accelerate tumor aggressiveness by promoting EMT via activation of PI3K/Akt and IL-6/STAT3 pathways.
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China; Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China; Department of Pharmacy, No. 309 Hospital of PLA, Beijing, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Meng
authors.affiliation: Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Xu-Tao
authors.initials: XT
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Xin-Li
authors.initials: XL
authors.lastname: Liu
authors.affiliation: Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Fan
authors.affiliation: Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Li
authors.affiliation: Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China.
authors.forename: Xiao-Hua
authors.initials: XH
authors.lastname: Liang
authors.affiliation: Institute of Materia Medica, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Jian-Bo
authors.initials: JB
authors.lastname: Wang
authors.affiliation: Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China.
authors.forename: Qi-Bing
authors.initials: QB
authors.lastname: Mei
authors.affiliation: Key Laboratory of Gastrointestinal Pharmacology of Chinese Materia Medica of the State Administration of Traditional Chinese Medicine, Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China. Electronic address: zhangf037@163.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Thoracic Surgery, Tangdu Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: zhangft@fmmu.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015203:Reproducibility of Results; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D014408:Biomarkers, Tumor; D015850:Interleukin-6; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; C116750:BAZ1B protein, human; D000092468:Bromodomain Containing Proteins
keywords: Epithelial–mesenchymal transition (EMT); IL-6/STAT3; Lung cancer; PI3K/Akt; WSTF