The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer

Abstract

// Zhongwu Li 1,2,* , Yanling Wang 1,2,* , Jing Qiu 1 , Qiang Li 1 , Chunping Yuan 1 , Wei Zhang 1 , Dongmiao Wang 1 , Jinhai Ye 2 , Hongbin Jiang 2 , Jianrong Yang 2 , Jie Cheng 1,2 1. Head Neck Cancer Center, Institute of Stomatology, Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China PRC 2. Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China PRC * These two authors contributed equally to this work. Correspondence: Jie Cheng, email: // Jianrong Yang, email: // Keywords : tongue squamous cell carcinoma, polycomb complex, EZH2, DZNep Received : October 14, 2013 Accepted : December 5, 2013 Published : December 7, 2013 Abstract EZH2, a core member of the Polycomb Repressor Complex 2 (PRC2), mediates transcriptional silencing by catalyzing the trimethylation of histone 3 lysine 27 (H3K27), which plays key roles in cancer initiation and progression. Here, we investigated the expression pattern and biological roles of EZH2 in tongue tumorigenesis by loss-of-function assays using small interference RNA and EZH2 inhibitor DZNep. Also we determined the therapeutic efficiency of DZNep against tongue cancer in vivo. We found that aberrantly overexpressed EZH2 was associated with pathological grade, cervical nodes metastasis and Ki-67 expression in tongue cancers. Elevated EZH2 correlated with shorter overall survival and showed significant and independent prognostic importance in patients with tongue cancer. Both genetic and pharmacological depletion of EZH2 inhibited cell proliferation, migration, invasion and colony formation and decreased CD44+ subpopulation probably in part through modulating p16, p21 and E-caherin. Moreover, DZNep enhanced the anticancer effects of 5-Fluorouracil. Furthermore, intratumoral EZH2 inhibition induced by DZNep intraperitoneal administration significantly attenuated tumor growth in a tongue cancer xenograft model. Taken together, our results indicate that EZH2 serves as a key driver with multiple oncogenic functions during tongue tumorigenesis and a new biomarker for tongue cancer diagnosis and prognostic prediction. These findings open up possibilities for therapeutic intervention against EZH2 in tongue cancer.