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, 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 -