The stress-responsive gene GADD45G is a functional tumor suppressor, with its response to environmental stresses frequently disrupted epigenetically in multiple tumors.
The CpG island of GADD45G was identified as a target sequence during the identification of hypermethylated genes using methylation-sensitive representational difference analysis combined with 5-aza-2'-deoxycytidine demethylation. Located at the commonly deleted region 9q22, GADD45G is a member of the DNA damage-inducible gene family. In response to stress shock, GADD45G inhibits cell growth and induces apoptosis. Same as other GADD45 members, GADD45G is ubiquitously expressed in all normal adult and fetal tissues. However, its transcriptional silencing or down-regulation and promoter hypermethylation were frequently detected in tumor cell lines, including 11 of 13 (85%) non-Hodgkin's lymphoma, 3 of 6 (50%) Hodgkin's lymphoma, 8 of 11 (73%) nasopharyngeal carcinoma, 2 of 4 (50%) cervical carcinoma, 5 of 17 (29%) esophageal carcinoma, and 2 of 5 (40%) lung carcinoma and other cell lines but not in any immortalized normal epithelial cell line, normal tissue, or peripheral blood mononuclear cells. The silencing of GADD45G could be reversed by 5-aza-2'-deoxycytidine or genetic double knockout of DNMT1 and DNMT3B, indicating a direct epigenetic mechanism. Aberrant methylation was further frequently detected in primary lymphomas although less frequently in primary carcinomas. Only one single sequence change in the coding region was detected in 1 of 25 cell lines examined, indicating that genetic inactivation of GADD45G is very rare. GADD45G could be induced by heat shock or UV irradiation in unmethylated cell lines; however, this stress response was abolished when its promoter becomes hypermethylated. Ectopic expression of GADD45G strongly suppressed tumor cell growth and colony formation in silenced cell lines. These results show that GADD45G can act as a functional new-age tumor suppressor but being frequently inactivated epigenetically in multiple tumors.
Ying
Jianming
J
Johns Hopkins Singapore, Singapore.
Srivastava
Gopesh
G
Hsieh
Wen-Son
WS
Gao
Zifen
Z
Murray
Paul
P
Liao
Shuen-Kuei
SK
Ambinder
Richard
R
Tao
Qian
Q
D000943:Antigens, Differentiation / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D019073:HT29 Cells; D006367:HeLa Cells; D006358:Hot Temperature; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D020014:K562 Cells; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000097642:GADD45 Proteins
D000943:Antigens, Differentiation; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D018797:Cell Cycle Proteins; D015254:DNA Modification Methylases; D000077209:Decitabine; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C086470:GADD45B protein, human; C485654:GADD45G protein, human