Abstract
BackgroundEpigenetics has been known to play a critical role in regulating the malignant phenotype. This study was designed to examine the expression of DOT1L (histone 3 lysine 79 methyltransferase) and H3K79 methylation in normal ovarian tissues and ovarian tumors and to explore the function of DOT1L and its underline mechanisms in ovarian cancer.MethodsThe expression of DOT1L and H3K79 methylation in 250 ovarian tumor samples and 24 normal ovarian samples was assessed by immunohistochemistry. The effects of DOT1L on cell proliferation in vitro were evaluated using CCK8, colony formation and flow cytometry. The DOT1L-targeted genes were determined using chromatin immune-precipitation coupled with high-throughput sequencing (ChIP-seq) and ChIP-PCR. Gene expression levels were measured by real-time PCR and immunoblotting. The effects of DOT1L on tumor growth in vivo were evaluated using an orthotopic ovarian tumor model.ResultsDOT1L expression and H3K79 methylation was significantly increased in malignant ovarian tumors. High DOT1L expression was associated with International Federation of Gynecology and Obstetrics (FIGO) stage, histologic grade, and lymphatic metastasis. DOT1L was an independent prognostic factor for the overall survival (OS) and progression-free survival (PFS) of ovarian cancer, and higher DOT1L expression was associated with poorer OS and PFS. Furthermore, DOT1L regulates the transcription of G1 phase genes CDK6 and CCND3 through H3K79 dimethylation; therefore, blocking DOT1L could result in G1 arrest and thereby impede the cell proliferation in vitro and tumor growth in vivo.ConclusionsOur findings first demonstrate that DOT1L over-expression has important clinical significance in ovarian cancer and also clarify that it drives cell cycle progression through transcriptional regulation of CDK6 and CCND3 through H3K79 methylation, suggesting that DOT1L might be potential target for prognostic assessment and therapeutic intervention in ovarian cancer.
Highlights
Epigenetics has been known to play a critical role in regulating the malignant phenotype
Our findings first demonstrated that Ovarian cancer (OC) patients expressing high level of Disruptor of telomeric silencing-1-like (DOT1L) have poorer overall survival (OS) and progression-free survival (PFS) compared with those with low DOT1L expression, and DOT1L expression can be regarded as an independent prognostic factor
DOT1L regulates the transcription of G1 phase genes CDK6 and CCND3 through H3K79 dimethylation, thereby knocking down of DOT1L could result in G1 arrest and impede the cell proliferation and tumor progression both in vitro and in vivo
Summary
Epigenetics has been known to play a critical role in regulating the malignant phenotype. The discovery of novel biomarkers with high sensitivity and specificity for the early diagnosis and target therapies of OC will help to improve the prognosis of this disease. Epigenetic changes, such as DNA methylation and histone post-translational modifications, are major contributing factors for carcinogenesis [4]. A few recent publications have reported that DOT1L plays crucial roles in leukemia, and in solid tumors, such as breast cancer, esophageal squamous cell carcinoma, colorectal cancer, prostate cancer, and gastric cancer [13,14,15,16,17,18,19]. DOT1L inhibitors have shown effective suppression of proliferation, migration, and invasion of breast cancer [20]
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