Abstract
BackgroundWe previously identified that the CpG island-associated promoter of the novel lincRNA ZNF300P1 (also known as LOC134466) is frequently hypermethylated and silenced in ovarian cancer tissues. However, the function of ZNF300P1 was unknown. In this report we demonstrate that ZNF300P1 is involved in the regulation of key cell cycle and cell motility networks in human ovarian surface epithelial cells, and may play a role in promoting metastasis in ovarian cancer cells.MethodsWe applied methylated DNA immunoprecipitation on whole genome promoter tiling arrays and Sequenom assays to examine methylation status of ZNF300P1 in multiple ovarian cancer cell lines, as well as in normal ovarian and ovarian tumor tissues. Transcript profiling was used to investigate the effects of ZNF300P1 suppression in ovarian cancer cells. We utilized siRNA knockdown in normal ovarian surface epithelial cells and performed cellular proliferation, migration and adhesion assays to validate and explore the profiling results.ResultsWe demonstrate that ZNF300P1 is methylated in multiple ovarian cancer cell lines. Loss of ZNF300P1 results in decreased cell proliferation and colony formation. In addition, knockdown of the ZNF300P1 transcript results in aberrant and less persistent migration in wound healing assays due to a loss of cellular polarity. Using an ex vivo peritoneal adhesion assay, we also reveal a role for ZNF300P1 in the attachment of ovarian cancer cells to peritoneal membranes, indicating a potential function of ZNF300P1 expression in metastasis of ovarian cancer cells to sites within the peritoneal cavity.ConclusionOur findings further support ZNF300P1 as frequently methylated in ovarian cancer and reveal a novel function for ZNF300P1 lincRNA expression in regulating cell polarity, motility, and adhesion and loss of expression may contribute to the metastatic potential of ovarian cancer cells.
Highlights
We previously identified that the CpG island-associated promoter of the novel lincRNA ZNF300P1 is frequently hypermethylated and silenced in ovarian cancer tissues
The transcript profiles from the same study showed that this hypermethylation was associated with repression of gene expression (Additional file 1: Figure S1A), suggesting that regional epigenetic silencing may occur near ZNF300P1 in ovarian cancer
We reveal a novel role for ZNF300P1 in the adhesion of ovarian cancer cells to the peritoneal membrane, suggesting a potential function in ovarian cancer metastasis
Summary
We previously identified that the CpG island-associated promoter of the novel lincRNA ZNF300P1 ( known as LOC134466) is frequently hypermethylated and silenced in ovarian cancer tissues. Epithelial ovarian cancer (EOC) comprises 90% of all ovarian cancer cases [2]. Type II EOC, known as high-grade serous ovarian cancer, comprises 70% of EOC cases [4] and is characterized by rapid growth with no identified precursor lesions, and genome instability (p53 loss) [5]. The molecular events underlying Type II EOC remain poorly understood, and despite initial response to chemotherapy, these tumors often recur with chemoresistance. Despite recent advances in surgery and adjuvant chemotherapeutics, the overall five-year survival rate for EOC remains at only 40%, in part due to common and rapid peritoneal spread of disease, indicating the need to understand the genetic and epigenetic events underlying EOC progression
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