DNA methyltransferase 1 (DNMT1) plays a critical role in breast cancer progression. However, the epigenetic mechanism regulating DNMT1 expression remains largely unknown. Epigenetic regulation of DNMT1 was assessed in 85 invasive ductal carcinomas from BRCA1 mutation carriers. Association between clinicopathological features and DNMT1 promoter methylation was determined using Fisher’s exact test. Univariate analysis of survival was performed using the Kaplan-Meier method. Multivariate Cox regression analysis was performed to identify the independent prognostic factors for overall survival. Hypermethylated E2F transcription factor 1 (E2F1) motif is a key regulatory element for the DNMT1 gene in BRCA1-mutated breast cancer. Mechanistically, the abnormal E2F1 motif methylation-mediated loss of active histone H3 lysine 9 acetylation (H3K9ac) and transcription factor E2F1 enrichment synergistically inhibited the transcription of DNMT1. Clinicopathological data indicated that the hypermethylated E2F1 motif was associated with histological grade, lymph node, Ki67 and E-cadherin status; univariate survival and multivariate analyses demonstrated that lymph node metastasis was an independent and reliable prognostic factor for BRCA1-mutated breast cancer patients. Our findings imply that genetic (such as BRCA1 mutation) and epigenetic mechanisms (such as DNA methylation, histone modification, transcription factor binding) are jointly involved in the malignant progression of DNMT1-related breast cancer.

Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial ovarian cancer (EOC) development remains to be elucidated. In this study, the biological functions of FTO were verified in vitro and in vivo. The m6A modification and the binding sites of SNAI1 mRNA were confirmed by m6A RNA immunoprecipitation (MeRIP) and RIP experiments. The actinomycin D assay was used to test the stability of RNA. We found that FTO was downregulated with increased m6A levels in EOC. Reduced expression of FTO was associated with a higher FIGO stage in patients with EOC. Mechanistically, FTO decreased the m6A level and stability of SNAI1 mRNA, causing downregulation of SNAI1 and inhibiting epithelial–mesenchymal transition (EMT). Furthermore, FTO-mediated downregulation of SNAI1 expression depended on IGF2BP2, which acted as an m6A reader binding to the 3′ UTR region of SNAI1 mRNA to promote its stability. In conclusion, FTO inhibits SNAI1 expression to attenuate the growth and metastasis of EOC cells in an m6A-IGF2BP2-dependent manner. Our findings suggest that the FTO-IGF2BP2-SNAI1 axis is a potential therapeutic target in EOC.

The solute carrier (SLC) family is the largest group of membrane transporters, but their functions in ovarian cancer (OV) remain unclear. We analyzed SLC family members with amino acids-transporting functions in OV. The mRNA expression levels and prognostic values of SLCs in OV were analyzed in the Gene Expression Profiling Interactive Analysis and Kaplan-Meier Plotter database. Solute carrier family 7 member 2 (SLC7A2), which showed differential expression and the most significant prognostic value, was selected for further analyses. The cBioPortal database, Gene Set Enrichment Analysis and Weighted Correlation Network Analysis were used to explore the potential functions and molecular mechanisms of SLC7A2 in OV. Validations in our own samples and in Gene Expression Omnibus datasets were conducted. Functional validation in OV cell lines was carried out. In total, 73 SLC family members were analyzed. Seven members were upregulated while 11 members were downregulated in OV and 15 members were protective factors for prognosis while 12 members were risk factors. SLC7A2 was downregulated in OV, and it was positively associated with prognosis. Knockdown of SLC7A2 promoted viability, invasion and migration of OV cells. These SLC family members and in particular SLC7A2 represented novel biomarkers for diagnosis and treatment for OV.

Breast cancer 1 (BRCA1) and autophagy both play a significant role in drug resistance. However, little is known about the dynamic cross talk between BRCA1 and autophagy in the regulation of drug sensitivity. Here, we investigated the drug resistance‐associated regulation of BRCA1 in epithelial ovarian cancer stem cells (EOCSCs). The results indicated that BRCA1 could regulate drug resistance in EOCSCs. Autophagy played a significant role in the stemness maintenance and was a key mechanism underlying the survival against chemotherapy in EOCSCs. Further investigation found that BRCA1 could regulate drug resistance of EOCSCs through autophagy. Meanwhile, changes in the level of autophagy provided feedback regarding the expression of BRCA1. Inhibition of autophagy activity could effectively reduce the resistance of EOCSCs caused by BRCA1. In addition, BRCA1 was able to regulate cellular apoptosis and cell cycle progression under the action of cisplatin through autophagy, indirectly affecting the drug sensitivity of EOCSCs. The present results highlight a novel relationship between BRCA1 and autophagy, which may provide insight into the etiology of BRCA1‐associated ovarian cancer, and improve our understanding of resistance mechanisms in ovarian cancer.

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Background: Poly (ADP-ribose) polymerase 1 (PARP1) overexpression plays a critical role in ovarian cancer progression and the clinical development of PARP1 inhibitors to treat BRCA-mutated ovarian cancer has advanced rapidly. However, the mechanism regulating PARP1 expression remains unknown. Alterations in gene expression mediated by promoter methylation are being increasingly recognized and have frequently been reported in ovarian cancer. We therefore investigated the methylation status of the PARP1 promoter region and its correlation with PARP1 expression in BRCA-mutated ovarian cancer. Methods: DNA from BRCA-mutated serous ovarian cancer samples and adjacent normal ovarian tissues were analyzed by bisulfite sequence using primers focusing on the CpG island in the promoter region of PARP1. Expression levels of PARP1 were assessed by immunohistochemistry and real-time PCR. Results: Serous ovarian cancer tissues displayed decreased DNA methylation in the promoter region of PARP1 compared to normal tissue, and methylation intensity correlated inversely with PARP1 mRNA levels. More importantly, E26 transformation-specific (ETS) defined CpG sites were significantly less methylated in ovarian cancer samples. Conclusions: These results indicate that hypomethylation of the promoter region, especially around the ETS motif might play a role in the upregulation of PARP1 expression in the progression of ovarian cancer.