Abstract
Aberrant DNA methylation is considered to play a critical role in the chemoresistance of epithelial ovarian cancer (EOC). In this study, we explored the relationship between hypermethylation of the Mahogunin Ring Finger 1 (MGRN1) gene promoter and primary chemoresistance and clinical outcomes in high-grade serous ovarian cancer (HGSOC) patients. The MALDI-TOF mass spectrometry assays revealed a strong association between hypermethylation of the MGRN1 upstream region and platinum resistance in HGSOC patients. Spearman’s correlation analysis revealed a significantly negative connection between the methylation level of MGRN1 and its expression in HGSOC. In vitro analysis demonstrated that knockdown of MGRN1 reduced the sensitivity of cells to cisplatin and that expression of EGR1 was significantly decreased in SKOV3 cells with low levels of MGRN1 expression. Similarly, EGR1 mRNA expression was lower in platinum-resistant HGSOC patients and was positively correlated with MGRN1 mRNA expression. Kaplan-Meier analyses showed that high methylation of the MGRN1 promoter region and low expression of MGRN1 were associated with worse survival of HGSOC patients. In multivariable models, low MGRN1 expression was an independent factor predicting poor outcome. Furthermore, low expression of EGR1 was also been confirmed to be significantly related to the poor prognosis of HGSOC patients by Kaplan-Meier. The hypermethylation of the MGRN1 promoter region and low expression of MGRN1 were associated with platinum resistance and poor outcomes in HGSOC patients, probably by altering EGR1 expression.
Highlights
Due to the lack of initial symptoms and sensitive screening methods, approximately 70% of women with epithelial ovarian cancer (EOC) are diagnosed at an advanced stage of disease [1, 2]; EOC is the most lethal gynecologic malignancy in China [3, 4]
The analysis revealed that methylation levels of two CpG sites (-1107 and -1097) were significantly higher in the tumor tissues of platinum-resistant high-grade serous ovarian cancer (HGSOC) patients than in those of platinum-sensitive HGSOC patients (P=0.01, 0.04, Figure 1B)
Based on the results of previous representation bisulfite sequencing (RRBS) analysis, we found that the methylation level of the Mahogunin Ring Finger 1 (MGRN1) upstream region (-1148 to -1064) was significantly higher in the platinum-resistant HGSOC patients
Summary
Due to the lack of initial symptoms and sensitive screening methods, approximately 70% of women with epithelial ovarian cancer (EOC) are diagnosed at an advanced stage of disease [1, 2]; EOC is the most lethal gynecologic malignancy in China [3, 4]. Abnormal methylation of DNA has been considered to play an important role during the development of acquired chemoresistance in EOC patients [13]. There are currently very few studies about the effect of DNA methylation on the development of intrinsic resistance in EOC patients. In our previous study, reduced representation bisulfite sequencing (RRBS) analysis showed that the promoter region of the Mahogunin Ring Finger 1 (MGRN1) gene had abnormal hypermethylation in high-grade serous ovarian cancer (HGSOC) patients with platinum resistance [14]. Ubiquitin-mediated proteolysis has played a crucial role in controlling protein level homeostasis and regulating the cell cycle, cell proliferation, apoptosis and DNA damage responses, which are involved in tumorigenesis, tumor development, prognosis and drug resistance [16]. A study by Dugué et al suggests that hypomethylation of MGRN1 CpG sites in peripheral blood DNA is associated with the development of sporadic and familiar breast cancer [17]
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