Epigenetic regulation of ARHI in breast and ovarian cancer cells.

Abstract

ARHI (Ras homologue member I) encodes a 26-kDa GTPase with 50-60% amino acid homology to Ras and Rap. ARHI and Ras share similar GTP/GDP binding domains, but exert opposite functions. ARHI is one of the first reported tumor suppressors in the ras superfamily. ARHI is expressed consistently in normal breast and ovarian epithelial cells, but not in breast or ovarian cancers. The loss of ARHI can be related to tumor progression. Reexpression of ARHI induces apoptosis of breast and ovarian cancer cells by a caspase-independent, calpain-dependent pathway. ARHI is consistently expressed in normal breast and ovarian epithelial cells but is dramatically downregulated in more then 70% of breast and ovarian cancers. ARHI is maternally imprinted with methylation of the three CpG islands in the maternal allele of normal cells. ARHI is expressed only from the paternal allele whose three CpG islands are not methylated. Loss of ARHI expression can occur through a genetic event, with loss of heterozygosity observed in 40% of breast, ovarian, and pancreatic cancers; but it can also occur through epigenetic mechanisms, including DNA methylation, histone deacetylation, histone methylation, and transcriptional regulation. Our data suggest that acetylation and methylation of chromatin associated with the ARHI promoter leads to loss of both ARHI expression and the ability to suppress tumor growth. Changes in chromatin that silence ARHI may be driven by methylation-dependent and -independent pathways. Reactivation of both the silenced paternal and imprinted maternal alleles can be achieved by demethylation and inhibition of histone deacetylation.

• Authors: Yinhua Yu, Satoshi Fujii, Jiuhong Yuan, Robert Z Luo, Lin Wang, Jiaju Bao, Mitsutaka Kadota, Mitsuo Oshimura, Sharon R Dent, Jean-Pierre Issa, Robert C Bast Jr
• Journal: Annals of the New York Academy of Sciences (Ann N Y Acad Sci) Vol. 983 Pg. 268-77 (Mar 2003) ISSN: 0077-8923 [Print] United States
• PMID: 12724231 (Publication Type: Journal Article, Review)

Chemical References

• DIRAS3 protein, human
• Histones
• rho GTP-Binding Proteins

Topics

• Acetylation
• Apoptosis (genetics)
• Breast Neoplasms (genetics, pathology)
• Cell Division (genetics)
• DNA Methylation
• Female
• Gene Expression Regulation, Neoplastic (genetics)
• Gene Silencing
• Genes, Tumor Suppressor
• Genomic Imprinting
• Histones (metabolism)
• Humans
• Loss of Heterozygosity
• Ovarian Neoplasms (genetics, pathology)
• Promoter Regions, Genetic
• Tumor Cells, Cultured
• rho GTP-Binding Proteins (genetics)