Prognostic and therapeutic value of disruptor of telomeric silencing-1-like (DOT1L) expression in patients with ovarian cancer

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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0400-8) contains supplementary material, which is available to authorized users.

Somatostatin receptor subtype 1 as a potential diagnostic marker and therapeutic target in prostate cancer

“…This indicates that sst1 activation may inhibit cell proliferation via negative regulation of PI3K/AKT pathway, which is a common mechanism that has been previously reported with other components of the SST system . In line with this concept, treatment with this sst1 agonist also inhibited CCND3 expression, which has been previously linked with proliferation promotion and is modulated by AKT phosphorylation, which could suggest a novel mechanism of action for BIM‐23926 sst1 agonists in PCa (ie, sst1/pAKT/CCND3). On the other hand, the effect exerted by this sst1 agonist on 22Rv1 cells does not seem to be mediated by the promotion of apoptosis since p53 mRNA expression levels were not altered by this treatment; however, further studies would be necessary before a clear conclusion can be reached in this regard.…”

Characterization of Copy Number Variations in Oral Cavity Squamous Cell Carcinoma Reveals a Novel Role for MLLT3 in Cell Invasiveness

“…Dot1 and its mammalian homolog, Dot1L, possess histone methyltranferase activity toward histone H3K79 , which regulates diverse cellular processes such as transcriptional regulation, cell cycle regulation, DNA damage response, differentiation, and development of leukemia . Recently, several publications have reported that Dot1L plays a crucial role in leukemia as well as in solid tumors, such as breast cancer, esophageal squamous cell carcinoma, colorectal cancer, prostate cancer, gastric cancer, and ovarian cancer . Furthermore, Dot1L is a drug target for mixed‐lineage leukemia (MLL) gene‐rearranged leukemia .…”

“…Furthermore, Dot1L is a drug target for mixed‐lineage leukemia (MLL) gene‐rearranged leukemia . Several Dot1L inhibitors have shown effective suppression of proliferation, migration, and invasion in ovarian cancer and breast cancer . However, in the current literature, the role of Dot1L on OSCC tumorigenesis and progression has not yet been investigated.…”

The role of DOT1L in the proliferation and prognosis of gastric cancer

“…In addition, the vital functioning of DOT1L in the mixed lineage leukemia (MLL)-rearranged leukemia has been shown [8], and thus DOT1L-targeted inhibitors have been used in rearranged leukemia [9]. In solid tumors, DOT1L is also involved in its progression, such as breast cancer [10], ovarian cancer [11], and lung cancer [12]. However, to date, the therapeutic value and the prognostic impact of DOT1L in GC has not been evaluated.…”