Snail and Slug collaborate on EMT and tumor metastasis through miR-101-mediated EZH2 axis in oral tongue squamous cell carcinoma

// Min Zheng 1, 2, * , Ya-ping Jiang 1, * , Wei Chen 1, 3, * , Kai-de Li 1 , Xin Liu 1 , Shi-yu Gao 1 , Hao Feng 1 , Sha-sha Wang 1 , Jian Jiang 1 , Xiang-rui Ma 1 , Xiao Cen 1 , Ya-jie Tang 4 , Yu Chen 1 , Yun-feng Lin 1 , Ya-ling Tang 1, 5 , Xin-hua Liang 1, 6 1 State Key Laboratory of Oral Diseases West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041, People's Republic of China 2 Department of Stomatology, Zhoushan Hospital, Zhoushan, Zhejiang 316000, People's Republic of China 3 Department of Oral and Maxillofacial Surgery, Tianjin Stomatological Hospital, Tianjin 300041, People's Republic of China 4 Key Laboratory of Fermentation Engineering (Ministry of Education), Hubei University of Technology, Wuhan 430068, People's Republic of China 5 Department of Oral Pathology, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041, People's Republic of China 6 Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology (Sichuan University), Chengdu Sichuan 610041, People's Republic of China * These authors have contributed equally to this work Correspondence to: Ya-ling Tang, e-mail: tangyaling@scu.edu.cn Xin-hua Liang, e-mail: lxh88866@scu.edu.cn ; drliangxinhua@aliyun.com Keywords: Oral tongue squamous cell carcinoma (OTSCC), Epithelial-mesenchymal transition (EMT), miR-101, Snail, Slug Received: November 03, 2014 Accepted: January 25, 2015 Published: February 09, 2015 ABSTRACT microRNAs(miRNAs) can regulate epithelial-mesenchymal transition (EMT) through transcription factors, however, little is known whether EMT transcription factors can modulate miRNAs and further induce EMT and cancer metastasis. Here we show that overexpression of Snail and Slug leads to a mesenchymal phenotype and morphology and enhances cell invasion along with stem cell properties in squamous cell carcinoma of oral tongue (OTSCC) cells. Repression of miR-101 expression by Snail and Slug is essential for Snail/Slug-induced malignant phenotypes. The suppression of miR-101 subsequently activates EZH2, the sole histone methyltransferase, inducing EMT, migration and invasion of OTSCC cells. Importantly, co-overexpression of Slug and Snail correlates with poor survival and elevated EZH2 expression in two independent patient cohorts of OTSCC specimens. These findings defined a Snail and Slug/miR-101/EZH2 pathway as a novel regulatory axis of EMT-mediated-microRNA signaling.