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: Cong Peng, Xiaoting Jia, Yan Xiong, Jiang Yin, Nan Li, Yingen Deng, Kai Luo, Qiong Zhang, Chengkun Wang, Zhijie Zhang, Guopei Zheng, Zhimin He
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 24 Pg. 20177-89 (Aug 21 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26036631 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 14-3-3 Proteins
• Catenins
• Homeodomain Proteins
• Transcription Factors
• ZEB1 protein, human
• Zinc Finger E-box-Binding Homeobox 1
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Glycogen Synthase Kinase 3

Topics

• 14-3-3 Proteins (genetics, metabolism)
• Carcinoma, Squamous Cell (genetics)
• Catenins (genetics, metabolism)
• Glycogen Synthase Kinase 3 (genetics, metabolism)
• Glycogen Synthase Kinase 3 beta
• Homeodomain Proteins (genetics, metabolism)
• Humans
• Signal Transduction
• Tongue Neoplasms (genetics)
• Transcription Factors (genetics, metabolism)
• Transfection
• Zinc Finger E-box-Binding Homeobox 1