PX-478 2HCl In the present study LLY

In the present study, LLY-507 suppressed the proliferation of HGSOC PX-478 2HCl via induction of apoptosis. Moreover, the colony-formation assay showed the long-term effects of SMYD2 inhibitors on HGSOC. It has been reported that LLY-507 induces an anti-tumor effect in several types of cancers in vitro, including esophageal, liver, and breast cancer cell lines, in a dose-dependent manner [23]. The results of the present study suggest that LLY-507 has a therapeutic potential for the treatment of HGSOC. This is the first study to report the anti-tumor effect of LLY-507 against HGSOC cells. PARP inhibitors have attracted considerable attention as one of the major molecular-targeted therapeutics for inhibiting DNA damage response. Currently, there are several completed phase III trials of olaparib, such as the SOLO1 and SOLO2 studies. The SOLO1 study was a randomized, double-blind, phase III trial to examine the efficacy of olaparib as a maintenance therapy for advanced ovarian cancer, primary peritoneal cancer, or fallopian-tube cancer patients with BRCA1, BRCA2, or BRCA1/2 mutations. The results showed that the risk of disease progression or death was 70% lower with olaparib than with placebo [24]. The SOLO2 trial was performed to examine the anti-tumor effect of olaparib as a maintenance therapy for patients with platinum-sensitive, recurrence, and germline BRCA-mutated ovarian cancer. The results revealed that olaparib significantly improved progression-free survival compared with placebo in patients with a germline BRCA1 or BRCA2 (BRCA1/2) mutation and platinum-sensitive, relapsed ovarian cancer [25]. Olaparib has been clinically applied for treating patients with certain recurrent ovarian cancers associated with BRCA1/2 mutations in the United States. In Japan, it has been used to treat patients with platinum-sensitive relapsed ovarian cancer [25]. Our results suggest that combination therapy with small-molecule SMYD2 inhibitors, such as LLY-507 and olaparib can be a plausible strategy for effective treatment of HGSOC. It has been reported that SMYD2 methylates PARP1 and promotes its activity in cancer cells [12]. The combination effect of SMYD2 inhibitor and PARP inhibitor may be due to the decrease in the activity of methylated PARP and inhibition of PARP activity (Fig. 4C). There are some limitations in this study. First, biomarkers for SMYD2 inhibitors need to be identified. Second, ex vivo experiments might be needed to further examine the anti-tumor effect of LLY-507 in HGSOC. Third, we need to clarify the involvement of histone and non-histone methylation by SMYD2 in HGSOC.
Conflicts of interest
Acknowledgments The authors thank Miss Kaori Tomita (Research assistant, Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo) for her support and assistance; Editage for English language editing (http://englishediting.editage.com/).
Introduction Epigenetic regulation is essential for cellular function and diversity. Major mechanisms include DNA methylation and histone protein modifications. Histone methylation is an epigenetic mark leading to either transcriptional activation or repression [1]. G9a (EHMT2) is a histone methyltransferase that dimethylates lysine 9 at histone 3 (H3K9me2), thus reducing transcription. G9a consists of a catalytic active SET domain, ankyrin repeats for protein–protein interactions and a nuclear localization signal [2]. Physiologically, G9a is required for correct differentiation of embryonic stem cells and immune cells [2]. G9a depletion resulted in global methylation loss specifically at euchromatin—a unique feature suggesting that G9a controls active promoter regions [2]. Overly active G9a contributes to development and progression of various cancers and is directly involved in cancer metabolism, metastasis, cell survival and response to hypoxia [2], [3], [4], [5]. Currently, only a few studies have investigated G9a in human tumors demonstrating higher expression of G9a in cancer tissues compared to healthy controls [3], [5], [6], [7], [8], [9], [10]. Moreover, high G9a expression was associated with unfavorable clinicopathological parameters and poor survival in lung, ovarian, endometrial cancer as well as in esophageal squamous cell and hepatocellular carcinoma (HCC) [3], [7], [8], [9], [10].