br Introduction Ovarian cancer patients have the highest mor

Introduction Ovarian cancer patients have the highest mortality rate amongst patients with gynecologic cancers. The 10-year survival rate of ovarian cancer patients is <30%. High-grade serous ovarian carcinoma (HGSOC) accounts for 70–80% of ovarian cancer-related deaths. Most patients with HGSOC are diagnosed at advanced stages of the disease [1]. Genomic analysis of HGSOC has revealed genetic mutations in some genes, such as TP53 and BRCA1/2. Among these genes, the rate of somatic TP53 mutations observed in HGSOC was over 95%. Some HGSOC patients have germline mutations in BRCA1/2, which is related to hereditary breast and ovarian cancer (HBOC) syndrome. As a new molecular targeted therapy for HGSOC, the PARP inhibitor, olaparib, was developed for BRCA1/2 mutated HGSOC. The PARP inhibitor is a pharmacological inhibitor of the enzyme PARP, which is involved in DNA repair. PARP inhibitor can selectively induce synthetic lethality in cancer Ergosterol with BRCA1/2 mutation [2]. Several studies have indicated the role of dysregulation of histone methylation in carcinogenesis and cancer progression [3,4]. Several histone methyltransferases (HMTs) and demethylases are frequently upregulated in many types of cancers [5,6]. Our previous study showed that the HMT, SUV39H2, conferred therapeutic resistance to lung cancer cells [7]. In addition, we have reported that the overexpression of the HMT, EZH2, is observed in endometrial cancer cells, and that the knockdown of EZH2 expression and treatment with an EZH2-selective inhibitor suppress cancer growth and induce apoptosis [8]. Thus, there is substantial evidence suggesting that the inhibition of HMTs is a promising and novel strategy for cancer therapy. Another HMT, SMYD2, has been identified as a member of the SMYD family and is known to function as an oncogene. It is a SET and MYND domain-containing histone (lysine) methyltransferase that methylates histone proteins H3K4 and H3K36 associated with active transcription [9]. SMYD2 also methylates various types of non-histone proteins, including p53, Rb, HSP90, ERα, EML4-ALK, β-catenin, and poly ADP ribose polymerase (PARP)1, thereby regulating various cellular function [[10], [11], [12], [13], [14], [15]].
Materials and methods
Results
Discussion In the present study, we found that SMYD2 was overexpressed in HGSOC tissue samples compared to its levels in the normal ovary tissue samples. Our in vitro study results further suggested that the higher expression of SMYD2 enhanced the proliferation of HGSOC cells. In addition, suppression of SMYD2 increased the proportion of apoptotic cells. Overall, selective inhibition of SMYD2 demonstrated that SMYD2 is a potent therapeutic target for HGSOC treatment. Previously, we showed that some HMTs play vital roles in carcinogenesis in humans [7,8]. Other studies have also suggested the involvement of HMTs in malignant alterations of cells in humans [5,6]. Studies have shown that SMYD2 expression is upregulated in several carcinomas, such as gastric, breast, and bladder cancers [11,19,20]. Some studies have suggested that knockdown of SMYD2 suppresses the proliferation of various types of cancer cells [11]. Consistent with the previous results, we found that knockdown of SMYD2 suppressed cell proliferation in HGSOC cells. We also found that knockdown of SMYD2 induced apoptotic cells that increased in the sub G1 phase in the cell cycle analysis. In addition, knockdown of SMYD2 increased the cleavage of PARP, which is a marker of apoptosis. Studies have reported that the mechanism of anti-tumor effect involves SMYD2 suppression, leading to the induction of cell cycle arrest in the G1/G0 phase in various types of cancers [19,20]. It has also been reported that knockdown of SMYD2 with siRNA enhances p53-mediated apoptosis via reducing p53 methylation [10,20]. However, there might be other mechanisms of apoptosis induction in HGSOC because HGSOC is characterized by TP53 mutation, which involves loss of function [2]. Further, SMYD2 methylates several non-histone proteins, such as PTEN. PTEN is known to be a tumor suppressor gene and is known to induce apoptosis [21]. Therefore, another possible mechanism of apoptosis is that the knockdown of SMYD2 decreases PTEN methylation and increases PTEN activity [22].