OPCML is a broad tumor suppressor for multiple carcinomas and lymphomas with frequently epigenetic inactivation.
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 in multiple tumors including nasopharyngeal carcinoma (NPC). OPCML, located at 11q25, is one of the downregulated genes we identified through digital expression subtraction.


RESULTS
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 -independent growth of carcinoma cells with endogenous silencing.


CONCLUSIONS
Thus, through functional epigenetics, we identified OPCML as a broad tumor suppressor, which is frequently inactivated by methylation in multiple malignancies.
Cui
Yan
Y
State Key Laboratory in Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology, Hong Kong Cancer Institute, Chinese University of Hong Kong, Hong Kong, China.
Ying
Ying
Y
van Hasselt
Andrew
A
Ng
Ka Man
KM
Yu
Jun
J
Zhang
Qian
Q
Jin
Jie
J
Liu
Dingxie
D
Rhim
Johng S
JS
Rha
Sun Young
SY
Loyo
Myriam
M
Chan
Anthony T C
AT
Srivastava
Gopesh
G
Tsao
George S W
GS
Sellar
Grant C
GC
Sung
Joseph J Y
JJ
Sidransky
David
D
Tao
Qian
Q
D017398:Alternative Splicing; D002277:Carcinoma / Q000235:genetics*; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D058851:GPI-Linked Proteins; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D014644:Genetic Variation; D006801:Humans; D019656:Loss of Heterozygosity; D008223:Lymphoma / Q000235:genetics*; D008297:Male; D009303:Nasopharyngeal Neoplasms / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012016:Reference Values; D014158:Transcription, Genetic
D015815:Cell Adhesion Molecules; D058851:GPI-Linked Proteins; D009419:Nerve Tissue Proteins; C059785:OPCML protein, human