TY - JOUR
T1 - OPCML is a broad tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation
AU - Cui, Yan
AU - Ying, Ying
AU - Van Hasselt, Andrew
AU - Ng, Ka Man
AU - Yu, Jun
AU - Zhang, Qian
AU - Jin, Jie
AU - Liu, Dingxie
AU - Rhim, Johng S.
AU - Rha, Sun Young
AU - Loyo, Myriam
AU - Chan, Anthony T.C.
AU - Srivastava, Gopesh
AU - Tsao, George S.W.
AU - Sellar, Grant C.
AU - Sung, Joseph J.Y.
AU - Sidransky, David
AU - Tao, Qian
PY - 2008/8/20
Y1 - 2008/8/20
N2 - Background: Identification of tumor suppressor genes (TSGs) silenced by CpG methylation uncovers the molecular mechanism of tumorigenesis and potential tumor biomarkers. Loss of heterozygosity at 11q25 is common multiple tumors including nasopharyngeal carcinoma (NPC). OPCML, located at 11q25, is one of the downregulated genes we identified through digital expression subtraction. Methodology/Principal Findings: Semi-quantitative RT-PCR showed frequent OPCML silencing in NPC and other common tumors, with no homozygous deletion detected by multiplex differential DNA-PCR. Instead, promoter methylation of OPCML was frequently detected in multiple carcinoma cell lines (nasopharyngeal, esophageal, lung, gastric, colon, liver, breast, cervix, prostate), lymphoma cell lines (non-Hodgkin and Hodgkin lymphoma, nasal NK/T-cell lymphoma) and primary tumors, but not in any non-tumor cell line and seldom weakly methylated in normal epithelial tissues. Pharmacological and genetic demethylation restored OPCML expression, indicating a direct epigenetic silencing. We further found that OPCML is stress-responsive, but this response is epigenetically impaired when its promoter becomes methylated. Ecotopic expression of OPCML led to significant inhibition of both anchorage-dependent and -indendent growth of carcinoma cells with endogenous silencing. Conlusions/Significance: Thus, through functional epigenetics, we identified OPCML as a broad tumor suppressor, which is frequently inactivated by methylation in multiple malignancies.
AB - Background: Identification of tumor suppressor genes (TSGs) silenced by CpG methylation uncovers the molecular mechanism of tumorigenesis and potential tumor biomarkers. Loss of heterozygosity at 11q25 is common multiple tumors including nasopharyngeal carcinoma (NPC). OPCML, located at 11q25, is one of the downregulated genes we identified through digital expression subtraction. Methodology/Principal Findings: Semi-quantitative RT-PCR showed frequent OPCML silencing in NPC and other common tumors, with no homozygous deletion detected by multiplex differential DNA-PCR. Instead, promoter methylation of OPCML was frequently detected in multiple carcinoma cell lines (nasopharyngeal, esophageal, lung, gastric, colon, liver, breast, cervix, prostate), lymphoma cell lines (non-Hodgkin and Hodgkin lymphoma, nasal NK/T-cell lymphoma) and primary tumors, but not in any non-tumor cell line and seldom weakly methylated in normal epithelial tissues. Pharmacological and genetic demethylation restored OPCML expression, indicating a direct epigenetic silencing. We further found that OPCML is stress-responsive, but this response is epigenetically impaired when its promoter becomes methylated. Ecotopic expression of OPCML led to significant inhibition of both anchorage-dependent and -indendent growth of carcinoma cells with endogenous silencing. Conlusions/Significance: Thus, through functional epigenetics, we identified OPCML as a broad tumor suppressor, which is frequently inactivated by methylation in multiple malignancies.
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U2 - 10.1371/journal.pone.0002990
DO - 10.1371/journal.pone.0002990
M3 - Article
C2 - 18714356
AN - SCOPUS:52049115449
SN - 1932-6203
VL - 3
JO - PLoS One
JF - PLoS One
IS - 8
M1 - e2990
ER -