Epigenetic silencing of TCEAL7 (Bex4) in ovarian cancer.
Epigenetic silencing by hypermethylation of CpGs represents a mechanism of inactivation of tumor suppressors. Here we report on the cloning of a novel candidate tumor suppressor gene TCEAL7 inactivated by methylation in ovarian cancer. TCEAL codes for a 1.35 kb transcript that was previously reported to be downregulated in ovarian cancer by cDNA microarray and suppression subtraction cDNA (SSH) analyses. This report focuses on the elucidation of mechanisms associated with TCEAL7 downregulation. Expression of TCEAL7 is downregulated in a majority of ovarian tumors and cancer cell lines but induced by 5-aza-2'-deoxycytidine treatment in a dose-dependant manner, implicating methylation as a mechanism of TCEAL7 inactivation. Sequence analyses of bisufite-modified genomic DNA from somatic cell hybrids with either the active or the inactive human X chromosome reveal that TCEAL7 is subjected to X chromosome inactivation. Loss of TCEAL7 expression in primary tumors and cell lines correlates with methylation of a CpG site within the promoter. In vitro methylation of the CpG site suppresses promoter activity whereas selective demethylation of the SmaI site attenuates the suppression. Finally, re-expression of TCEAL7 in cancer cell lines induces cell death and reduces colony formation efficiency. These data implicate TCEAL7 as a cell death regulatory protein that is frequently inactivated in ovarian cancers, and suggest that it may function as a tumor suppressor.
Chien
Jeremy
J
Division of Experimental Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic/Foundation, 200 First Street, SW Rochester, MN 55905, USA.
Staub
Julie
J
Avula
Rajeswari
R
Zhang
Heyu
H
Liu
Wanguo
W
Hartmann
Lynn C
LC
Kaufmann
Scott H
SH
Smith
David I
DI
Shridhar
Viji
V
D000595:Amino Acid Sequence; D051017:Apoptosis Regulatory Proteins; D001483:Base Sequence; D045744:Cell Line, Tumor; D041321:Chromosomes, Human, X; D017124:Conserved Sequence; D019175:DNA Methylation; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics*; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000235:genetics*; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
D051017:Apoptosis Regulatory Proteins; C410727:BEX3 protein, human; D018076:DNA, Complementary; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011506:Proteins; C503109:TCEAL7 protein, human