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.
Highlights
Oral cancer is the sixth most common cancers worldwide with more than 70% of cases occurring in developing countries, accounting for approximately 3% of all malignancies in both sexes [1]
EZH2 is overexpressed in tongue SCC (TSCC) cell lines and clinical specimens
Our results indicated that addition of MG132 partially prevented the reduction of EZH2 induced by Deazaneplanocin A (DZNep) (Fig.2D), implying that DZNep inhibited EZH2 probably through increased protein degradation rather than transcriptional repression
Summary
Oral cancer is the sixth most common cancers worldwide with more than 70% of cases occurring in developing countries, accounting for approximately 3% of all malignancies in both sexes [1]. The major risks for this malignancy include human papillomavirus (HPV) infection, smoking and heavy alcohol consumption [2]. The overweighing majority of oral cancer is diagnosed as squamous cell carcinoma (SCC) and mostly arises from tongue. Despite tremendous advancement in multimodal therapies for oral cancer including surgery, chemotherapy and radiotherapy over the past decades, the 5-year survival rate of oral SCC has not increased too much. Local relapse and cervical lymph node metastasis are the most prevalent factor affecting patients’ survival [3]. Some small or early oral carcinoma lesions may have occult nodal metastasis and behave aggressively at their initial stages. Many patients are diagnosed at an advanced stage in their initial clinical visits and died without successful treatments. Many oncogenes and tumor suppressors have been identified as key players underlying oral tumorigenesis, no optimal and commonly-accepted biomarkers have been established www.impactjournals.com/oncotarget
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