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The Stress-Responsive Gene GADD45G Is a Functional Tumor Suppressor, with Its Response to Environmental Stresses Frequently Disrupted Epigenetically in Multiple Tumors

Authors' Affiliations: ¹ Johns Hopkins Singapore, Singapore; ² Cancer Epigenetics Laboratory, Department of Clinical Oncology, Sir YK Pao Cancer Center, Chinese University of Hong Kong; ³ Department of Pathology, University of Hong Kong, Hong Kong; ⁴ Sydney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland; ⁵ Department of Pathology, Peking University Health Science Center, Beijing, China; ⁶ Cancer Research UK Institute for Cancer Studies, University of Birmingham, Birmingham, United Kingdom; and ⁷ Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taiwan, China

Requests for reprints: Qian Tao, Department of Clinical Oncology, Sir YK Pao Cancer Center, Prince of Wales Hospital, Chinese University of Hong Kong, Room 315, Hong Kong. Phone: 852-2632-1340; Fax: 852-2648-8842; E-mail: qtao{at}clo.cuhk.edu.hk.

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.

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