Abstract
Jumonji domain-containing 6 (JMJD6) is a candidate gene associated with tumorigenesis, and JMJD6 overexpression predicts poor differentiation and unfavorable survival in some cancers. However, there are no studies reporting the expression of JMJD6 in ovarian cancer, and no JMJD6 inhibitors have been developed and applied to targeted cancer therapy research. In the present study, we found that the high expression of JMJD6 in ovarian cancer was correlated with poor prognosis in ovarian cancer. A potential inhibitor (SKLB325) was designed based on the crystal structure of the jmjC domain of JMJD6. This molecule significantly suppressed proliferation and induced apoptosis in a dose-dependent manner in SKOV3 cell lines as detected by CCK-8 cell proliferation assays and flow cytometry. A Matrigel endothelial tube formation assay showed that SKLB325 inhibited capillary tube organization and migration in HUVECs in vitro. We also observed that JMJD6 colocalized with p53 protein in the nucleus, with mRNA and protein expression of p53 as well as its downstream effectors significantly increasing both in vitro and in intraperitoneal tumor tissues treated with SKLB325. In addition, SKLB325 significantly reduced the intraperitoneal tumor weight and markedly prolonged the survival of tumor-bearing mice. Taken together, our findings suggest that JMJD6 may be a marker of poor prognosis in ovarian cancer and that SKLB325 may be a potential candidate drug for the treatment of ovarian cancer.
Highlights
IntroductionOvarian cancer is the principal cause of death among gynecological malignant tumors.[1,2,3] Mortality remains extraordinarily high, despite many studies on the mechanism of ovarian cancer[4] and many improvements in treatments for patients with ovarian cancer, including surgery, radiotherapy, chemotherapy and new biological therapies.[5,6,7] In addition, more than 70% of ovarian cancer patients are at advanced stages when initially diagnosed, and the 5-year survival rate is less than 30%.8 This terrible situation reflects a lack of novel, effective and feasible therapeutic approaches to treat ovarian cancer.JMJD6, a member of the Jumonji C (JMJC) domain-containing family of proteins, which is a lysine hydroxylase,[9,10] may regulate the transcriptional activity of p53 by hydroxylation of a lysine in the p53 C-terminal structural domain.[11,12,13,14] Initially, JMJD6 was studied as the phospholipid methionine receptor on the surface of phagocytic cells.[15,16,17] Subsequently, many studies showed that
The expression of JMJD6 was detected by tissue microarray immunohistochemical staining, and we found high expression of JMJD6 in ovarian cancer, which was correlated with poor prognosis
JMJD6 is a marker of poor prognosis in ovarian cancer We investigated the prognosis of JMJD6 expression in ovarian cancer
Summary
Ovarian cancer is the principal cause of death among gynecological malignant tumors.[1,2,3] Mortality remains extraordinarily high, despite many studies on the mechanism of ovarian cancer[4] and many improvements in treatments for patients with ovarian cancer, including surgery, radiotherapy, chemotherapy and new biological therapies.[5,6,7] In addition, more than 70% of ovarian cancer patients are at advanced stages when initially diagnosed, and the 5-year survival rate is less than 30%.8 This terrible situation reflects a lack of novel, effective and feasible therapeutic approaches to treat ovarian cancer.JMJD6, a member of the Jumonji C (JMJC) domain-containing family of proteins, which is a lysine hydroxylase,[9,10] may regulate the transcriptional activity of p53 by hydroxylation of a lysine in the p53 C-terminal structural domain.[11,12,13,14] Initially, JMJD6 was studied as the phospholipid methionine receptor on the surface of phagocytic cells.[15,16,17] Subsequently, many studies showed that. Ovarian cancer is the principal cause of death among gynecological malignant tumors.[1,2,3] Mortality remains extraordinarily high, despite many studies on the mechanism of ovarian cancer[4] and many improvements in treatments for patients with ovarian cancer, including surgery, radiotherapy, chemotherapy and new biological therapies.[5,6,7] In addition, more than 70% of ovarian cancer patients are at advanced stages when initially diagnosed, and the 5-year survival rate is less than 30%.8.
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