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Published on: August 23, 2019
REC8 is a novel tumor suppressor gene epigenetically robustly targeted by the PI3K pathway in thyroid cancer
Dingxie Liu1, Xiaopei Shen1, Guangwu Zhu1
1Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Abstract:
The role of the PI3K pathway in human cancer has been well established, but much of its molecular mechanism, particularly the epigenetic aspect, remains to be defined. We hypothesized that aberrant methylation and hence altered expression of certain unknown important genes induced by the genetically activated PI3K pathway signaling is a major epigenetic mechanism in human tumorigenesis. Through a genome-wide search for such genes that were epigenetically controlled by the PI3K pathway in thyroid cancer cells, we found a wide range of genes with broad functions epigenetically targeted by the PI3K pathway. The most prominent among these genes was REC8, classically known as a meiotic-specific gene, which we found to be robustly down-regulated by the PI3K pathway through hypermethylation. REC8 hypermethylation was strongly associated with genetic alterations and activities of the PI3K pathway in thyroid cancer cell lines, thyroid cancer tumors, and some other human cancers; it was also associated with poor clinicopathological outcomes of thyroid cancer, including advanced disease stages and patient mortality. Demethylating the hypermethylated REC8 gene restored its expression in thyroid cancer cells in which the PI3K pathway was genetically over-activated and induced expression of REC8 protein inhibited the proliferation and colony formation of these cells. These findings are consistent with REC8 being a novel major bona fide tumor suppressor gene and a robust epigenetic target of the PI3K pathway. Aberrant inactivation of REC8 through hypermethylation by the PI3K pathway may represent an important mechanism mediating the oncogenic functions of the PI3K pathway.
Insights
The PI3K pathway epigenetically silences the REC8 gene via hypermethylation in human cancers, acting as a tumor suppressor. Restoring REC8 expression inhibits cancer cell growth, revealing a novel PI3K pathway mechanism.
Area of Science:
- Molecular Biology
- Cancer Epigenetics
- Oncology
Background:
- The phosphoinositide 3-kinase (PI3K) pathway is crucial in human cancer, but its epigenetic mechanisms, especially methylation, are not fully understood.
- Aberrant gene methylation driven by PI3K signaling is hypothesized to be a key epigenetic driver of tumorigenesis.
Purpose of the Study:
- To identify novel genes epigenetically regulated by the PI3K pathway in human cancers.
- To investigate the role of the meiotic gene REC8 in thyroid cancer and its connection to PI3K pathway activation.
Main Methods:
- Genome-wide screening in thyroid cancer cells to identify PI3K-pathway-controlled epigenetically regulated genes.
- Analysis of REC8 gene methylation, expression, and its association with PI3K pathway alterations in cancer cell lines and patient tumors.
- Functional studies involving gene demethylation and REC8 re-expression to assess effects on cancer cell proliferation and colony formation.
Main Results:
- A broad spectrum of genes were found to be epigenetically targeted by the PI3K pathway.
- REC8, a meiotic gene, was significantly downregulated by PI3K-mediated hypermethylation in thyroid and other cancers.
- REC8 hypermethylation correlated with PI3K pathway activity, advanced disease stages, and poorer patient outcomes.
- Demethylation of REC8 restored its expression and inhibited cancer cell proliferation and colony formation.
Conclusions:
- REC8 functions as a novel tumor suppressor gene epigenetically inactivated by the PI3K pathway through hypermethylation.
- PI3K-mediated REC8 silencing is a significant mechanism contributing to oncogenesis.
- Targeting REC8 epigenetic inactivation may offer a therapeutic strategy in PI3K-driven cancers.
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