Oncotarget

Research Papers:

REC8 is a novel tumor suppressor gene epigenetically robustly targeted by the PI3K pathway in thyroid cancer

Dingxie Liu _, Xiaopei Shen, Guangwu Zhu and Mingzhao Xing

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Oncotarget. 2015; 6:39211-39224. https://doi.org/10.18632/oncotarget.5391

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Abstract

Dingxie Liu1, Xiaopei Shen1, Guangwu Zhu1, Mingzhao Xing1

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

Correspondence to:

Mingzhao Xing, e-mail: mxing1@jhmi.edu

Keywords: REC8, thyroid cancer, tumor suppressor gene, methylation, thyroid tumorigenesis

Received: July 16, 2015     Accepted: October 02, 2015     Published: October 13, 2015

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.


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