Genomic loss of EZH2 leads to epigenetic modifications and overexpression of the HOX gene clusters in myelodysplastic syndrome
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Feng Xu1,*, Li Liu1,*, Chun-Kang Chang1, Qi He1, Ling-Yun Wu1, Zheng Zhang1, Wen-Hui Shi1, Juan Guo1, Yang Zhu1, You-Shan Zhao1, Shu-Cheng Gu1, Cheng-Ming Fei1, Xiao Li1
1Department of Hematology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
*These authors contributed equally to this work
Li Xiao, e-mail: [email protected]
Keywords: myelodysplastic syndrome, EZH2, H3K27 methylation, overexpression, HOX genes
Received: August 10, 2015 Accepted: January 01, 2016 Published: January 23, 2016
The role of EZH2 in cancer is complex and may vary depending on cancer type or stage. We examined the effect of altered EZH2 levels on H3K27 methylation, HOX gene expression, and malignant phenotype in myelodysplastic syndrome (MDS) cell lines and an in vivo xenograft model. We also studied links between EZH2 expression and prognosis in MDS patients. Patients with high-grade MDS exhibited lower levels of EZH2 expression than those with low-grade MDS. Low EZH2 expression was associated with high percentages of blasts, shorter survival, and increased transformation of MDS into acute myeloid leukemia (AML). MDS patients frequently had reductions in EZH2 copy number. EZH2 knockdown increased tumor growth capacity and reduced H3K27me3 levels in both MDS-derived leukemia cells and in a xenograft model. H3K27me3 levels were reduced and HOX gene cluster expression was increased in MDS patients. EZH2 knockdown also increased HOX gene cluster expression by reducing H3K27me3, and H3K27 demethylating agents increased HOX gene cluster expression in MDS-derived cell lines. These findings suggest genomic loss of EZH2 contributes to overexpression of the HOX gene clusters in MDS through epigenetic modifications.
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