Overexpression of EZH2 is associated with the poor prognosis in osteosarcoma and function analysis indicates a therapeutic potential.

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.

• Authors: Ranran Sun, Jacson Shen, Yan Gao, Yubing Zhou, Zujiang Yu, Francis Hornicek, Quancheng Kan, Zhenfeng Duan
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 25 Pg. 38333-38346 (Jun 21 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27223261 (Publication Type: Journal Article)

Chemical References

• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein

Topics

• Adult
• Apoptosis (physiology)
• Bone Neoplasms (genetics, metabolism, pathology, therapy)
• Cell Line, Tumor
• Cell Movement (physiology)
• Cell Proliferation (physiology)
• Enhancer of Zeste Homolog 2 Protein (antagonists & inhibitors, biosynthesis, genetics)
• Female
• Gene Knockdown Techniques
• Humans
• Male
• Neoplasm Invasiveness
• Osteosarcoma (genetics, metabolism, pathology, therapy)
• Prognosis
• Survival Analysis
• Tissue Array Analysis