Abstract
Osteosarcoma is a primary malignant bone tumor that has a poor prognosis due to local recurrence, metastasis, and chemotherapy resistance. Therefore, there is an urgent need to develop novel potential therapeutic targets for osteosarcoma. Enhancer of zeste homologue 2 (EZH2) is a member of the polycomb group of proteins, which has important functions in epigenetic silencing and cell cycle regulation. Overexpression of EZH2 has been found in several malignancies, however, its expression and the role of EZH2 in osteosarcoma is largely unknown. In this study, we examined EZH2 expression by immunohistochemistry in a large series of osteosarcoma tissues in association with tumor characteristics and patient outcomes. EZH2 expression was also analyzed in a microarray dataset of osteosarcoma. Results showed that higher expression of EZH2 was significantly associated with more aggressive tumor behavior and poor patient outcomes of osteosarcoma. We subsequently investigated the functional and therapeutic relevance of EZH2 as a target in osteosarcoma. Immunohistochemical analysis indicated that EZH2 expression was significantly associated with more aggressive tumor behavior and poorer patient outcomes of osteosarcoma. EZH2 silencing by siRNA inhibited osteosarcoma cell growth, proliferation, migration, and invasion. Moreover, suppression of EZH2 attenuated cancer stem cell functions. Similar results were observed in osteosarcoma cells treated with EZH2 specific inhibitor 3-deazaneplanocin A (DZNep), which exhausted cellular levels of EZH2. These results suggest that EZH2 is critical for the growth and metastasis of osteosarcoma, and an epigenetic therapy that pharmacologically targets EZH2 via specific inhibitors may constitute a novel approach to the treatment of osteosarcoma.
Highlights
Osteosarcoma is the most common primary malignant tumor of bone in young adults and adolescents
We found that Enhancer of zeste homologue 2 (EZH2) was constitutively highly expressed in osteosarcoma cell lines and tissues
Further correlation analyses revealed that abnormally high expression of EZH2 was positively correlated with increased aggressive and metastatic behavior, indicating that EZH2 expression may contribute to the progression of osteosarcoma by functioning as an oncogene
Summary
Osteosarcoma is the most common primary malignant tumor of bone in young adults and adolescents. Most of the current strategies have limited efficacy in the treatment of metastatic and recurrent osteosarcoma, which remains a major challenge in bone cancer fields. EZH2 is required for the stable transmission of gene expression patterns to progeny cells throughout development [6]. There is growing evidence that EZH2 can be regulated at transcriptional and post-translational levels in cancers [12, 13]. Limited expression of EZH2 was found in healthy tissues, while increased levels of EZH2 have been widely observed during tumorigenesis and progression [13]. Knockdown of EZH2 results in reduced proliferation, increased apoptosis, and diminished tumorigenicity in cancer cells [19,20,21]. The expression status and functional role of EZH2 in tumorigenesis and progression of osteosarcoma has not yet been fully investigated
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