DNA methylation-dependent repression of PDZ-LIM domain-containing protein 2 in colon cancer and its role as a potential therapeutic target.
Constitutive activation of the nuclear factor-kappaB (NF-kappaB) transcription factor plays a key role in chronic colonic inflammation and colon tumorigenesis. However, the mechanisms by which the tightly regulated NF-kappaB pathway becomes constitutively activated during colonic pathogenesis remain obscure. Here, we report that PDLIM2, an essential terminator of NF-kappaB activation, is repressed in various human colorectal cancer cell lines, suggesting one important mechanism for the constitutive activation of NF-kappaB. Indeed, expression of exogenous PDLIM2 inhibited constitutive NF-kappaB activation in these colorectal cancer cells. Importantly, the PDLIM2 expression was sufficient to suppress in vitro anchorage-independent growth and in vivo tumor formation of these malignant cells. We have further shown that the PDLIM2 repression involves promoter methylation. Accordingly, treatment of the colorectal tumor cell lines with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine restored PDLIM2 expression and resulted in growth arrest. These studies thus provide new mechanistic insights into colon tumorigenesis by identifying a novel tumor suppressor role for PDLIM2.
University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Zhaoxia
Z
Qu
Pengrong
P
Yan
Jing
J
Fu
Jing
J
Jiang
Michael J
MJ
Grusby
Thomas E
TE
Smithgall
Gutian
G
Xiao
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002448:Cell Adhesion / Q000235:genetics; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077209:Decitabine; D005260:Female; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D060588:LIM Domain Proteins; D051379:Mice; D016513:Mice, SCID; D008840:Microfilament Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D014183:Transplantation, Heterologous; D015854:Up-Regulation
D060588:LIM Domain Proteins; D008840:Microfilament Proteins; D016328:NF-kappa B; C502929:PDLIM2 protein, human; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine