title: The 14-3-3σ/GSK3β/β-catenin/ZEB1 regulatory loop modulates chemo-sensitivity in human tongue cancer.
abstract: Here we demonstrated that chemotherapy induced 14-3-3σ expression in tongue cancer (TC) cells and overexpressed 14-3-3σ sensitized TC cells to chemotherapy especially in multidrug resistant TC (MDR-TC) cells. In agreement, 14-3-3σ knockdown enhanced resistance of TC cells to chemotherapy. Mechanically, we found 14-3-3σ physically bound to GSK3β in protein level and the binding inhibited β-catenin signaling. Coincidentally, chemotherapy as well as 14-3-3σ overexpression led to increase of GSK3β protein level. Increased GSK3β protein sensitized TC cells to chemotherapy. Moreover, deregulation of 14-3-3σ/GSK3β/β-catenin axis led to overexpressed ZEB1 in TC cells, especially in MDR-TC cells. As a negative feedback loop, ZEB1 bond to 14-3-3σ promoter to enhance promoter hypermethylation in TC cells. Promoter hypermethylation resulted into the decrease of 14-3-3σ expression. Importantly, a positive correlation was observed between 14-3-3σ and GSK3β protein expression in TC tissues from patients receiving chemotherapy. High levels of 14-3-3σ and GSK3β were associated with better prognosis in TC patients.
authors.affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Peng
authors.affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department of Pharmacology, Guangzhou Institute of Snake Venom Research, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, Guangdong, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiong
authors.affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yin
authors.affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.
authors.forename: Yingen
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Luo
authors.affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.
authors.forename: Chengkun
authors.initials: C
authors.lastname: Wang
authors.affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.
authors.forename: Guopei
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: He
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D051177:Catenins / Q000235:genetics* / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D015398:Signal Transduction; D014062:Tongue Neoplasms / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D000071799:Zinc Finger E-box-Binding Homeobox 1
chemical_list: D048948:14-3-3 Proteins; D051177:Catenins; D018398:Homeodomain Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3
keywords: 14-3-3σ; GSK3β; chemosensitivity; tongue cancer; β-catenin