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

Dingxie Liu, Xiaopei Shen, Guangwu Zhu, Michael Mingzhao Xing

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)39211-39224
Number of pages14
JournalOncotarget
Volume6
Issue number36
DOIs
StatePublished - 2015

Fingerprint

Tumor Suppressor Genes
Phosphatidylinositol 3-Kinases
Thyroid Neoplasms
Epigenomics
Genes
Neoplasms
Methylation
Carcinogenesis
Genome
Cell Line
Mortality

Keywords

  • Methylation
  • REC8
  • Thyroid cancer
  • Thyroid tumorigenesis
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Oncology

Cite this

REC8 is a novel tumor suppressor gene epigenetically robustly targeted by the PI3K pathway in thyroid cancer. / Liu, Dingxie; Shen, Xiaopei; Zhu, Guangwu; Xing, Michael Mingzhao.

In: Oncotarget, Vol. 6, No. 36, 2015, p. 39211-39224.

Research output: Contribution to journalArticle

@article{995058bd168c42d0973efb527f9638d9,
title = "REC8 is a novel tumor suppressor gene epigenetically robustly targeted by the PI3K pathway in thyroid cancer",
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.",
keywords = "Methylation, REC8, Thyroid cancer, Thyroid tumorigenesis, Tumor suppressor gene",
author = "Dingxie Liu and Xiaopei Shen and Guangwu Zhu and Xing, {Michael Mingzhao}",
year = "2015",
doi = "10.18632/oncotarget.5391",
language = "English (US)",
volume = "6",
pages = "39211--39224",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "36",

}

TY - JOUR

T1 - REC8 is a novel tumor suppressor gene epigenetically robustly targeted by the PI3K pathway in thyroid cancer

AU - Liu, Dingxie

AU - Shen, Xiaopei

AU - Zhu, Guangwu

AU - Xing, Michael Mingzhao

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

KW - Methylation

KW - REC8

KW - Thyroid cancer

KW - Thyroid tumorigenesis

KW - Tumor suppressor gene

UR - http://www.scopus.com/inward/record.url?scp=84948798275&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84948798275&partnerID=8YFLogxK

U2 - 10.18632/oncotarget.5391

DO - 10.18632/oncotarget.5391

M3 - Article

C2 - 26472282

AN - SCOPUS:84948798275

VL - 6

SP - 39211

EP - 39224

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 36

ER -