TY - JOUR
T1 - Alteration of DNA methyltransferases contributes to 5′CpG methylation and poor prognosis in lung cancer
AU - Lin, Ruo Kai
AU - Hsu, Han Shui
AU - Chang, Jer Wei
AU - Chen, Chih Yi
AU - Chen, Jung Ta
AU - Wang, Yi Ching
N1 - Funding Information:
This work was supported in part by Grants NSC NHRI93A1-NSCLC06-5 and NSC93-2314-B-075-082 from the National Science Council (The Executive Yuan, Republic of China) and Grant DOH95-TD-G-111-004 from the Department of Health (The Executive Yuan, Republic of China).
PY - 2007/2
Y1 - 2007/2
N2 - Overexpression of DNA methyltransferases DNMT1, DNMT3a and DNMT3b has been reported in various cancers. However, physical binding of DNA methyltransferase (DNMT) to the hypermethylated promoter of tumor suppressor genes (TSGs) has never been demonstrated in tumor tissues. In addition, alteration of DNMT at the protein level has never been reported in the same series of cancer patients. By immunohistochemical analysis, we demonstrated that DNMT1, DNMT3a and DNMT3b proteins were highly expressed in a coordinate manner in lung tumors, particularly in smokers (P = 0.037, by the Fisher exact test). Patients with DNMT1 overexpression had a trend of poorer prognosis than those without such overexpression, and this prognostic significance was apparent in squamous carcinoma (SQ) patients (P = 0.041, by the log-rank test). Both DNMT1 and DNMT3b overexpressions correlated with hypermethylation in the TSG promoters, especially among smoking SQ patients (P = 0.012). To further explore the molecular mechanisms between altered TSGs promoter methylation and overexpression of DNMTs protein, we performed a tissue chromatin-immunoprecipitation polymerase chain reaction assay for lung tumors and showed that the methylated FHIT, p16INK4a and RARβ promoters were bound by both DNMT protein and methyl-CpG-binding protein 2. These data suggest that overexpression and strong binding of various DNMTs may result in promoter hypermethylation of multiple TSGs and ultimately lead to lung tumorigenesis and poor prognosis.
AB - Overexpression of DNA methyltransferases DNMT1, DNMT3a and DNMT3b has been reported in various cancers. However, physical binding of DNA methyltransferase (DNMT) to the hypermethylated promoter of tumor suppressor genes (TSGs) has never been demonstrated in tumor tissues. In addition, alteration of DNMT at the protein level has never been reported in the same series of cancer patients. By immunohistochemical analysis, we demonstrated that DNMT1, DNMT3a and DNMT3b proteins were highly expressed in a coordinate manner in lung tumors, particularly in smokers (P = 0.037, by the Fisher exact test). Patients with DNMT1 overexpression had a trend of poorer prognosis than those without such overexpression, and this prognostic significance was apparent in squamous carcinoma (SQ) patients (P = 0.041, by the log-rank test). Both DNMT1 and DNMT3b overexpressions correlated with hypermethylation in the TSG promoters, especially among smoking SQ patients (P = 0.012). To further explore the molecular mechanisms between altered TSGs promoter methylation and overexpression of DNMTs protein, we performed a tissue chromatin-immunoprecipitation polymerase chain reaction assay for lung tumors and showed that the methylated FHIT, p16INK4a and RARβ promoters were bound by both DNMT protein and methyl-CpG-binding protein 2. These data suggest that overexpression and strong binding of various DNMTs may result in promoter hypermethylation of multiple TSGs and ultimately lead to lung tumorigenesis and poor prognosis.
UR - http://www.scopus.com/inward/record.url?scp=33846111256&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33846111256&partnerID=8YFLogxK
U2 - 10.1016/j.lungcan.2006.10.022
DO - 10.1016/j.lungcan.2006.10.022
M3 - Article
C2 - 17140695
AN - SCOPUS:33846111256
SN - 0169-5002
VL - 55
SP - 205
EP - 213
JO - Lung Cancer
JF - Lung Cancer
IS - 2
ER -
