TY - JOUR
T1 - The chemokine receptor CXCR4 is regulated by DNA methylation in pancreatic cancer
AU - Sato, Norihiro
AU - Matsubayashi, Hiroyuki
AU - Fukushima, Noriyoshi
AU - Goggins, Michael
N1 - Funding Information:
This work was supported by the SPORE in Gastrointestinal Malignancies (CA62924) and the Michael Rolfe Foundation.
PY - 2005/1
Y1 - 2005/1
N2 - Despite the biological and clinical importance of the interaction between the chemokine receptor CXCR4 and its ligand CXCL12 (SDF-1α) in human cancers, little is known about transcriptional regulation of the CXCR4 gene. Although aberrant hypermethylation in cancer has been described typically in genes with tumor-suppressor properties, this epigenetic alteration has also been observed to affect potential cancer-promoting genes. We now demonstrate that DNA methylation influences CXCR4 expression in human pancreatic cancer. Gene expression profiling and reverse transcription-PCR identified a significant proportion of pancreatic cancer cell lines that displayed little or no CXCR4 mRNA expression. Using methylation-specific PCR, combined bisulfite restriction analysis, and bisulfite sequencing, we found the 5′ CpG islands of the CXCR4 gene to be unmethylated in normal pancreas, whereas promoter hypermethylation was detected in 45% (9 of 20) of pancreatic cancer cell lines and in 46% (46 of 100) of primary pancreatic adenocarcinomas. There was a significant inverse correlation between methylation and mRNA expression level of CXCR4 (P = 0.008) in a large panel of pancreatic cancer cell lines. Constitutive as well as inducible expression of CXCR4 could be restored in methylated cell lines pharmacologically using epigenetic modifying drugs. These findings demonstrate the first evidence for epigenetic regulation of CXCR4 in human cancers, providing new insights into the role of CXCR4/CXCL12 interactions in tumor progression.
AB - Despite the biological and clinical importance of the interaction between the chemokine receptor CXCR4 and its ligand CXCL12 (SDF-1α) in human cancers, little is known about transcriptional regulation of the CXCR4 gene. Although aberrant hypermethylation in cancer has been described typically in genes with tumor-suppressor properties, this epigenetic alteration has also been observed to affect potential cancer-promoting genes. We now demonstrate that DNA methylation influences CXCR4 expression in human pancreatic cancer. Gene expression profiling and reverse transcription-PCR identified a significant proportion of pancreatic cancer cell lines that displayed little or no CXCR4 mRNA expression. Using methylation-specific PCR, combined bisulfite restriction analysis, and bisulfite sequencing, we found the 5′ CpG islands of the CXCR4 gene to be unmethylated in normal pancreas, whereas promoter hypermethylation was detected in 45% (9 of 20) of pancreatic cancer cell lines and in 46% (46 of 100) of primary pancreatic adenocarcinomas. There was a significant inverse correlation between methylation and mRNA expression level of CXCR4 (P = 0.008) in a large panel of pancreatic cancer cell lines. Constitutive as well as inducible expression of CXCR4 could be restored in methylated cell lines pharmacologically using epigenetic modifying drugs. These findings demonstrate the first evidence for epigenetic regulation of CXCR4 in human cancers, providing new insights into the role of CXCR4/CXCL12 interactions in tumor progression.
KW - CXCR4
KW - Chemokine receptor
KW - Methylation
KW - Pancreatic cancer
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U2 - 10.4161/cbt.4.1.1378
DO - 10.4161/cbt.4.1.1378
M3 - Article
C2 - 15662133
AN - SCOPUS:24644501261
SN - 1538-4047
VL - 4
SP - 77
EP - 83
JO - Cancer Biology and Therapy
JF - Cancer Biology and Therapy
IS - 1
ER -