GADD45 Deregulation in Cancer: Frequently Methylated Tumor Suppressors and Potential Therapeutic Targets

In this issue of Clinical Cancer Research , Ying et al. ([1][1]) have investigated the hypothesis that GADD45γ , a member of the GADD45 family originally identified as a growth arrest– and DNA damage–inducible gene, could serve as a functional tumor suppressor gene, and moreover, as a

[1]  Marie Joseph,et al.  NF-κB-mediated repression of growth arrest- and DNA-damage-inducible proteins 45α and γ is essential for cancer cell survival , 2004 .

[2]  R. Singal,et al.  Methylation of Promoter Proximal-transcribed Sequences of an Embryonic Globin Gene Inhibits Transcription in Primary Erythroid Cells and Promotes Formation of a Cell Type-specific Methyl Cytosine Binding Complex* , 2002, The Journal of Biological Chemistry.

[3]  E. Prokhortchouk,et al.  Methyl-CpG binding proteins and cancer: are MeCpGs more important than MBDs? , 2002, Oncogene.

[4]  E. Scarano,et al.  DNA Methylation , 1973, Nature.

[5]  Kazushige Yamaguchi,et al.  Clinicopathological significance of abnormalities in Gadd45 expression and its relationship to p53 in human pancreatic cancer. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[6]  M. Tsao,et al.  Identification of 27 5′ CpG islands aberrantly methylated and 13 genes silenced in human pancreatic cancers , 2004, Oncogene.

[7]  Mutsuhiro Takekawa,et al.  Regulation of MTK1/MEKK4 Kinase Activity by Its N-Terminal Autoinhibitory Domain and GADD45 Binding , 2002, Molecular and Cellular Biology.

[8]  J. Herman,et al.  SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity , 2001, Nature Genetics.

[9]  Francesca Zazzeroni,et al.  Induction of gadd45β by NF-κB downregulates pro-apoptotic JNK signalling , 2001, Nature.

[10]  A. Kaneda,et al.  Identification of silencing of nine genes in human gastric cancers. , 2002, Cancer research.

[11]  F. Christians,et al.  Induction of GADD45 and JNK/SAPK-Dependent Apoptosis following Inducible Expression of BRCA1 , 1999, Cell.

[12]  W. Farrell,et al.  Loss of expression of the growth inhibitory gene GADD45γ, in human pituitary adenomas, is associated with CpG island methylation , 2004, Oncogene.

[13]  Manel Esteller,et al.  DNA methylation: a profile of methods and applications. , 2002, BioTechniques.

[14]  T. Libermann,et al.  Constitutive activation of nuclear factor kappaB p50/p65 and Fra-1 and JunD is essential for deregulated interleukin 6 expression in prostate cancer. , 2003, Cancer research.

[15]  A. Jubb,et al.  Methylation and colorectal cancer , 2001, The Journal of pathology.

[16]  D. Takai,et al.  Methylation‐Sensitive Representational Difference Analysis and Its Application to Cancer Research , 2003, Annals of the New York Academy of Sciences.

[17]  A. Bird,et al.  Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Long Yu,et al.  GADD45γ, down-regulated in 65% Hepatocellular Carcinoma (HCC) from 23 Chinese patients, inhibits cell growth and induces cell cycle G2/M arrest for Hepatoma Hep-G2 cell lines , 2003, Molecular Biology Reports.

[19]  R. Pazdur,et al.  Approval Summary: Azacitidine for Treatment of Myelodysplastic Syndrome Subtypes , 2005, Clinical Cancer Research.

[20]  P. Laird Early detection: The power and the promise of DNA methylation markers , 2003, Nature Reviews Cancer.

[21]  A. Fornace,et al.  Cell signalling (communication arising): Cell survival and a Gadd45-factor deficiency , 2003, Nature.

[22]  A. Fornace,et al.  Cell signalling: cell survival and a Gadd45-factor deficiency. , 2003, Nature.

[23]  Qian Tao,et al.  The Stress-Responsive Gene GADD45G Is a Functional Tumor Suppressor, with Its Response to Environmental Stresses Frequently Disrupted Epigenetically in Multiple Tumors , 2005, Clinical Cancer Research.

[24]  S. Cross,et al.  CpG islands and genes. , 1995, Current opinion in genetics & development.

[25]  T. Ushijima,et al.  Detection and interpretation of altered methylation patterns in cancer cells , 2005, Nature Reviews Cancer.

[26]  A. Bird,et al.  Number of CpG islands and genes in human and mouse. , 1993, Proceedings of the National Academy of Sciences of the United States of America.