Histone demethylase KDM2B upregulates histone methyltransferase EZH2 expression and contributes to the progression of ovarian cancer in vitro and in vivo

Abstract

Aberrant histone methylation contributes to the progression and development of many tumors. Histone methylation is a dynamic process regulated by both histone demethylase and histone methyltransferase, which ultimately alters the levels of gene transcription. However, the relationship between histone demethylase and histone methyltransferase, as well as their regulatory mechanisms in ovarian cancer development, is still unclear. Lysine-specific demethylase 2B (KDM2B) is a key demethylase of H3K36me3 and H3K4me3 that regulates gene expression and plays a role in tumorigenesis via epigenetic mechanisms. To determine the expression pattern of KDM2B in ovarian neoplasms, we analyzed the mRNA and protein levels of KDM2B and the histone methyltransferase enhancer of zester homolog 2 (EZH2) in normal, benign, borderline, and malignant ovarian tissue samples. We found that KDM2B expression was gradually increased in ovarian tumors, with the highest expression found in the malignant ovarian tissues, and the differences in KDM2B expression among the different International Federation of Gynecology and Obstetrics stages and pathological grades/types were statistically significant. Moreover, KDM2B expression was positively correlated with EZH2 expression in ovarian tissues. To determine the role of KDM2B in tumorigenesis in vitro and in vivo, we silenced KDM2B expression in ovarian cancer cells using the KDM2B short hairpin RNA expression lentivirus and established a nude mouse xenograft model. Downregulation of endogenous KDM2B decreased the expression of EZH2 and reduced the proliferation and migration of ovarian cancer cells. Loss of KDM2B suppressed ovarian tumor formation in vivo. Our results suggest that KDM2B plays an important role in the tumorigenesis of ovarian cancer, with a possible mechanism of increasing the expression of the oncogene EZH2; this indicates that certain histone methyltransferase may be positively regulated by certain histone demethylase in the epigenetic regulation of ovarian tumors. KDM2B may be a novel therapeutic target for the clinical treatment of ovarian cancer.

Keywords:

• ovarian cancer
• KDM2B
• EZH2
• epigenetic regulation
• tumor formation

Acknowledgments

This study was funded by National Natural Science Foundation of China (No 81360389), the National Natural Science Foundation of Guangxi (2012GXNSFAA053086), and the Self-financing Project of the Guangxi Health Department (Z2013026). Yan Kuang and Fangfang Lu are co-first authors for this study.

Disclosure

The authors report no conflicts of interest in this work.