RIL, a LIM gene on 5q31, is silenced by methylation in cancer and sensitizes cancer cells to apoptosis.
Gene silencing associated with promoter methylation can inactivate tumor suppressor genes (TSG) in cancer. We identified RIL, a LIM domain gene mapping to 5q31, a region frequently deleted in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), as methylated in 55 of 79 (70%) of cancer cell lines tested. In a variety of primary tumors, we found RIL methylation in 55 of 92 (60%) cases, with highest methylation in AML and colon cancer, and in 30 of 83 (36%) MDS samples, whereas normal tissues showed either absence or substantially lower levels of methylation, which correlates with age. RIL is ubiquitously expressed but silenced in methylated cancers and could be reactivated by the hypomethylating agent 5-aza-2'-deoxycytidine. Restoring RIL expression in colon cancer cells by stable transfection resulted in reduced cell growth and clonogenicity and an approximately 2.0-fold increase in apoptosis following UV exposure. In MDS, RIL methylation is a marker of adverse prognosis independent of chromosome 5 and 7 deletions. Our data suggest that RIL is a good candidate TSG silenced by hypermethylation in cancer.
Boumber
Yanis A
YA
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe, Houston, TX 77030, USA.
Kondo
Yutaka
Y
Chen
Xuqi
X
Shen
Lanlan
L
Gharibyan
Vazganush
V
Konishi
Kazuo
K
Estey
Elihu
E
Kantarjian
Hagop
H
Garcia-Manero
Guillermo
G
Issa
Jean-Pierre J
JP
D017209:Apoptosis / Q000235:genetics*; D049109:Cell Proliferation; D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D018899:CpG Islands; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D020868:Gene Silencing; D045325:HCT116 Cells; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D060588:LIM Domain Proteins; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D021141:Nucleic Acid Amplification Techniques; D011379:Prognosis; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; C486247:PDLIM4 protein, human