Oncotarget

Research Papers:

The 14-3-3σ/GSK3β/β-catenin/ZEB1 regulatory loop modulates chemo-sensitivity in human tongue cancer

Cong Peng _, Xiaoting Jia, Yan Xiong, Jiang Yin, Nan Li, Yingen Deng, Kai Luo, Qiong Zhang, Chengkun Wang, Zhijie Zhang, Guopei Zheng and Zhimin He

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Oncotarget. 2015; 6:20177-20189. https://doi.org/10.18632/oncotarget.3896

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Abstract

Cong Peng1,*, Xiaoting Jia1,*, Yan Xiong2, Jiang Yin1, Nan Li1, Yingen Deng1, Kai Luo1, Qiong Zhang1, Chengkun Wang1, Zhijie Zhang1, Guopei Zheng1, Zhimin He1

1Cancer Hospital and Cancer Research Institute of Guangzhou Medical University, Guangzhou 510095, Guangdong, China

2Department of Pharmacology, Guangzhou Institute of Snake Venom Research, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, Guangdong, China

* These authors have contributed equally to this work

Correspondence to:

Guopei Zheng, e-mail: [email protected]

Zhimin He, e-mail: [email protected]

Keywords: tongue cancer, 14-3-3σ, GSK3β, β-catenin, chemosensitivity

Received: March 10, 2015     Accepted: April 25, 2015     Published: May 08, 2015

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.


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