Epigenetic silencing of the GULP1 gene is key for ovarian cancer progression, suggesting it could be used as a prognostic biomarker for the disease, a study found.
The study, “Integrated transcriptomic and epigenomic analysis of ovarian cancer reveals epigenetically silenced GULP1,” conducted by researchers from Johns Hopkins University School of Medicine and Insilico Medicine, was published in Cancer Letters.
Epigenetics is the research field that studies how chemical modifications that affect gene expression are inherited, even though they are not encoded in the cell’s DNA.
Methylation, which consists on the chemical addition of a methyl group to a DNA sequence, is one of the most studied epigenetic modifications and is typically associated with gene silencing. Abnormal methylation patterns causing gene silencing are common in several cancer types and constitute one of the earliest signs of disease.
In ovarian cancer specifically, the discovery of methylated, low-expressed genes could lead to the identification of potential biomarkers to assess disease susceptibility, prognosis, and early detection. In addition, identifying the signaling pathways that could be directly affected by epigenetically inactivated genes also could unveil new therapeutic targets for clinical intervention.
To identify novel ovarian cancer-specific epigenetically silenced genes, researchers combined a genome-wide approach in ovarian cancer samples and normal ovarian cells with computational analysis to evaluate gene expression data.
To validate gene candidates, investigators then performed functional assays using a pharmacologic unmasking strategy in three malignant and three normal ovarian cell lines treated with a demethylating agent.
The analysis found a total of 43 ovarian cancer-specific methylated genes. Among the top five gene candidates — GULP1, CLIP4, BAMBI, NT5E, TGFβ2 — researchers selected GULP1 to conduct extended analyses.
“As GULP1 was reported to be involved in ovarian carcinogenesis, we focused on evaluating GULP1 methylation in different cohorts [groups] of primary OC [ovarian cancer] samples. We also performed functional characterization of GULP1 in ovarian carcinogenesis,” the investigators wrote.
GULP1 methylation was found in 34% of all ovarian cancer cases analyzed. Researchers validated their findings in another group of patients. In these, 40% of ovarian cancers, 12.5% of borderline tumors — those with both malignant and benign features — and 11% of cystadenomas had GULP1 methylation. This, however, was absent from normal ovarian samples.
“Furthermore, GULP1 methylation was associated with late stage disease, and worse overall survival, suggesting that GULP1 expression plays an important role in ovarian cancer pathogenesis [disease development],” researchers wrote in a press release.
Additional computer analysis shed light on how GULP1 methylation led to cancer progression. The team found that tumors with low GULP1 levels had an over-activation of signaling pathways involved in cell survival and proliferation.
“These pro-survival signaling axes play a crucial role in cancer initiation, progression and maintenance in various solid tumors, including ovarian cancer, and may contribute to acquisition of an aggressive [tumor] via inhibition of [cell death] and induction of cell proliferation,” the team wrote.
In accordance with these findings, depletion of GULP1 in malignant ovarian cell lines led to increased cancer cells’ proliferation, survival, and invasion, while GULP1 overproduction had the opposite effects, suggesting that GULP1 is required to maintain cell growth under control.
Altogether, these findings indicate that epigenetic regulation of GULP1 expression is important in ovarian cancer progression and emphasize its clinical value as a biomarker for disease prognosis.
“Although we did not investigate other possible mechanisms for GULP1 down-regulation, which may include microRNA-mediated silencing, transcriptional regulation, or homozygous deletions, a deeper understanding of the role of GULP1 methylation in the development of OC may offer additional possibilities for the management of OC,” investigators concluded.
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