Hypermethylation of the TGF-β target, ABCA1 is associated with poor prognosis in ovarian cancer patients

Abstract

BackgroundThe dysregulation of transforming growth factor-β (TGF-β) signaling plays a crucial role in ovarian carcinogenesis and in maintaining cancer stem cell properties. Classified as a member of the ATP-binding cassette (ABC) family, ABCA1 was previously identified by methylated DNA immunoprecipitation microarray (mDIP-Chip) to be methylated in ovarian cancer cell lines, A2780 and CP70. By microarray, it was also found to be upregulated in immortalized ovarian surface epithelial (IOSE) cells following TGF-β treatment. Thus, we hypothesized that ABCA1 may be involved in ovarian cancer and its initiation.ResultsWe first compared the expression level of ABCA1 in IOSE cells and a panel of ovarian cancer cell lines and found that ABCA1 was expressed in HeyC2, SKOV3, MCP3, and MCP2 ovarian cancer cell lines but downregulated in A2780 and CP70 ovarian cancer cell lines. The reduced expression of ABCA1 in A2780 and CP70 cells was associated with promoter hypermethylation, as demonstrated by bisulfite pyro-sequencing. We also found that knockdown of ABCA1 increased the cholesterol level and promoted cell growth in vitro and in vivo. Further analysis of ABCA1 methylation in 76 ovarian cancer patient samples demonstrated that patients with higher ABCA1 methylation are associated with high stage (P = 0.0131) and grade (P = 0.0137). Kaplan-Meier analysis also found that patients with higher levels of methylation of ABCA1 have shorter overall survival (P = 0.019). Furthermore, tissue microarray using 55 ovarian cancer patient samples revealed that patients with a lower level of ABCA1 expression are associated with shorter progress-free survival (P = 0.038).ConclusionsABCA1 may be a tumor suppressor and is hypermethylated in a subset of ovarian cancer patients. Hypermethylation of ABCA1 is associated with poor prognosis in these patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-014-0036-2) contains supplementary material, which is available to authorized users.

Morphologic and molecular changes in the placenta: what we can learn from environmental exposures

“…A global reduction in DNA methylation was also detected in ART extraembryonic tissues at E7.5 using methylated DNA immunoprecipitation (MeDIP) (12). Similar to results of imprinted genes, human ART placentas also demonstrate lower CpG methylation at select non-imprinted genes (31,38). …”

Redox biology and the interface between bioenergetics, autophagy and circadian control of metabolism

“…These changes occurred in parallel with a decrease in inflammatory markers such as IL-6 and TNFα, potentially via direct transcriptional regulation. This is not limited to arthritis and a connection between HDACi and cancer treatment has identified the potential role for epigenetic regulation of Nrf2 and precision medicine for treating colon cancer [64]. The metabolic contribution to this combined pathway is further supported by studies where hyperglycemia could additionally alter histone H3 via methylation at key regions of Nrf2-mediated transcriptional regulation [65], suggesting a mechanistic link between nutrient utilization and epigenetic control of key antioxidant defense pathways.…”

DNA methylation changes in epithelial ovarian cancer histotypes

“…Many studies cite mainly serous tumors (~ 80–60%), but include all histotypes in the analysis [77–79], others do not specify histotype [80–82], while others cite no differences between histotypes but have very small numbers of samples with which to conclude this [83–85,160]. There are studies that have focused on the CC and ENEOC histotypes [86–88] and HGS EOC [48], and it is hoped that future studies continue to consider histotype in their analyses.…”

“…In EOC, methylation of PLK2 is associated with transcriptional silencing and may be associated with a risk of relapse following chemotherapy [117,118]. Other genes in which methylation has been implicated in response to therapy by targeted studies include HIN1, HERV-K, DLEC1 and CDH1 in CC EOC [88,113], and ESR1 [80], HSulf-1 [119], FBOXO32 [120], ABCA1 [82], SFRP [79], CABIN1 [121], TGBFB1 [122,123] and HOXA11 [84] in EOC.…”