ABSTRACT
The POTE gene family consists of 14 homologous genes localized to autosomal pericentromeres, and a sub-set of POTEs are cancer-testis antigen (CTA) genes. POTEs are over-expressed in epithelial ovarian cancer (EOC), including the high-grade serous subtype (HGSC), and expression of individual POTEs correlates with chemoresistance and reduced survival in HGSC. The mechanisms driving POTE overexpression in EOC and other cancers is unknown. Here, we investigated the role of epigenetics in regulating POTE expression, with a focus on DNA hypomethylation. Consistent with their pericentromeric localization, Pan-POTE expression in EOC correlated with expression of the pericentromeric repeat NBL2, which was not the case for non-pericentromeric CTAs. POTE genomic regions contain LINE-1 (L1) sequences, and Pan-POTE expression correlated with both global and POTE-specific L1 hypomethylation in EOC. Analysis of individual POTEs using RNA-seq and DNA methylome data from fallopian tube epithelia (FTE) and HGSC revealed that POTEs C, E, and F have increased expression in HGSC in conjunction with DNA hypomethylation at 5' promoter or enhancer regions. Moreover, POTEs C/E/F showed additional increased expression in recurrent HGSC in conjunction with 5' hypomethylation, using patient-matched samples. Experiments using decitabine treatment and DNMT knockout cell lines verified a functional contribution of DNA methylation to POTE repression, and epigenetic drug combinations targeting histone deacetylases (HDACs) and histone methyltransferases (HMTs) in combination with decitabine further increased POTE expression. In summary, several alterations of the cancer epigenome, including pericentromeric activation, global and locus-specific L1 hypomethylation, and locus-specific 5' CpG hypomethylation, converge to promote POTE expression in ovarian cancer.
Subject(s)
Carcinoma, Ovarian Epithelial/genetics , DNA Methylation , Ovarian Neoplasms/genetics , Proteins/genetics , Up-Regulation , Cell Line, Tumor , Epigenesis, Genetic , Female , Gene Expression Regulation, Neoplastic , Humans , Long Interspersed Nucleotide Elements , Promoter Regions, GeneticABSTRACT
The POTE family includes 14 genes in three phylogenetic groups. We determined POTE mRNA expression in normal tissues, epithelial ovarian and high-grade serous ovarian cancer (EOC, HGSC), and pan-cancer, and determined the relationship of POTE expression to ovarian cancer clinicopathology. Groups 1 & 2 POTEs showed testis-specific expression in normal tissues, consistent with assignment as cancer-testis antigens (CTAs), while Group 3 POTEs were expressed in several normal tissues, indicating they are not CTAs. Pan-POTE and individual POTEs showed significantly elevated expression in EOC and HGSC compared to normal controls. Pan-POTE correlated with increased stage, grade, and the HGSC subtype. Select individual POTEs showed increased expression in recurrent HGSC, and POTEE specifically associated with reduced HGSC OS. Consistent with tumors, EOC cell lines had significantly elevated Pan-POTE compared to OSE and FTE cells. Notably, Group 1 & 2 POTEs (POTEs A/B/B2/C/D), Group 3 POTE-actin genes (POTEs E/F/I/J/KP), and other Group 3 POTEs (POTEs G/H/M) show within-group correlated expression, and pan-cancer analyses of tumors and cell lines confirmed this relationship. Based on their restricted expression in normal tissues and increased expression and association with poor prognosis in ovarian cancer, POTEs are potential oncogenes and therapeutic targets in this malignancy.
Subject(s)
Antigens, Neoplasm/genetics , Ovarian Neoplasms/genetics , Apoptosis Regulatory Proteins/genetics , Cell Line, Tumor , Female , Gene Expression Regulation, Neoplastic , Humans , Multigene Family , Ovarian Neoplasms/mortality , Ovarian Neoplasms/pathology , Survival AnalysisABSTRACT
BACKGROUND: Panniculectomy at time of gynecologic surgery is used to improve visualization and prevent major complications in morbidly obese patients. We examine the role of extended antibiotic prophylaxis in prevention of surgical site infections (SSI), specifically based on patient risk factors (hypertension, diabetes, smoking). METHODS: A prospective cohort study of all women who underwent panniculectomy at the time of gynecologic surgery from September 2014 to March 2016 at a university-affiliated hospital. The EAP cohort received standard antibiotics (cefazolin, 2 g) and continued oral antibiotic (doxycycline) for 10 days afterwards. Patients in this cohort were compared to historical controls from the same institution from 1990 to 2014. Specific attention was paid to the reduction of SSIs in patients with hypertension, diabetes, and a history of smoking. RESULTS: The mean age was 56.0 ± 12.6 years, and mean body mass index 44.5 ± 9.3 kg/m2 (range 31-63.4 kg/m2 ). The EAP cohort experienced fewer surgical-site infections overall, however these results were not significantly decreased from the historical controls, (13/56 [23.2%] vs 94/300 [31.3%]; P = 0.469). CONCLUSION: Though initially promising, extended antibiotic prophylaxis did not reduce surgical site infections in the obese women after indicated non-cosmetic panniculectomy at the time of gynecologic surgery.
