Disease relevance of DIRAS3

• Reexpression of NOEY2 through transfection suppresses clonogenic growth of breast and ovarian cancer cells [1].
• NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and breast carcinomas [1].
• Aberrant methylation was found in several breast cancer cell lines that exhibited decreased ARHI expression [2].
• While the retinoblastoma protein, pRB, alone had no effect on ARHI promoter activity, repression by E2F1, but not E2F4, was enhanced by the coexpression of pRB [3].
• When DCIS and invasive cancer were present in the same sample, ARHI was further down-regulated in 26% (6 of 23) of invasive carcinoma [4].
• Further analysis revealed that autophagic cell death was reduced when cultured human ovarian cancer cells in which ARHI had been re-expressed were treated with growth factors (IGF-1, M-CSF), angiogenic factors (VEGF, IL-8), and matrix proteins found in xenografts [5].

High impact information on DIRAS3

• Therefore, Rig and Noey2 may represent a new subfamily of Ras-like tumor suppressors [6].
• Rig bears 63% overall sequence homology to a recently described Ras-family member Noey2, a tumor suppressor in breast and ovarian tissue [6].
• Using differential display PCR, we have identified a gene [NOEY2, ARHI (designation by the Human Gene Nomenclature Committee)] with high homology to ras and rap that is expressed consistently in normal ovarian and breast epithelial cells but not in ovarian and breast cancers [1].
• To explore possible mechanisms that could silence ARHI expression, we have tested the importance of DNA methylation, histone acetylation and histone methylation in regulating ARHI expression [7].
• Chromatin immunoprecipitation assays revealed that histone H3 lysine 9/18 acetylation levels associated with ARHI in normal cells were significantly higher than those in breast cancer cell lines that lacked ARHI expression [7].

Chemical compound and disease context of DIRAS3

• Reactivation of ARHI expression in breast cancer cells is associated with increased histone H3 acetylation and decreased lysine 9 methylation of histone H3 [3].
• EXPERIMENTAL DESIGN: We analyzed ARHI expression in DCIS, invasive breast carcinoma, and adjacent normal breast epithelium from 64 formalin-fixed, paraffin-embedded DCIS specimens by both immunohistochemistry and in situ hybridization [4].

Biological context of DIRAS3

• Biochemistry and Biology of ARHI (DIRAS3), an Imprinted Tumor Suppressor Gene Whose Expression Is Lost in Ovarian and Breast Cancers [8].
• Methylation of CpG I alone partially inhibited promoter activity of ARHI [2].
• There are three CpG islands in the ARHI gene [2].
• Expression of ARHI from the paternal allele can be down-regulated by multiple mechanisms in addition to loss of heterozygosity [2].
• This article explores the role of DNA methylation in silencing ARHI expression [2].

Anatomical context of DIRAS3

• ARHI is associated at the cell membrane through its prenylation at the C-terminal cysteine residue [9].
• By histochemical analysis, ARHI expression was down-regulated in 41% (26 of 64) of DCIS and 70% (16 of 23) of invasive carcinomas comparing the specimens with adjacent normal breast epithelium [4].
• In addition, strong expression of the ARHI transgene was associated with greatly impaired mammary gland development and lactation, failure of ovarian folliculogenesis resulting in decreased fertility, loss of neurons in the cerebellar cortex, and impaired development of the thymus [10].
• Silencing of the maternally imprinted tumor suppressor ARHI contributes to follicular thyroid carcinogenesis [11].
• Since ARHI had been mapped to 1p31, a common deletion site in breast and ovarian cancer and male germ-cell tumors, in this study, we set out to define precisely the physical location of ARHI at 1p31 and to determine if this location lies within the smallest common region of deletion in breast and ovarian cancers [12].

Associations of DIRAS3 with chemical compounds

• Treatment with 5-aza-2'-deoxycytidine partially reactivated ARHI expression in cell lines with hypermethylation of CpG islands I and II but not in cell lines with partial methylation or hypomethylation of these CpG islands [2].
• Deletion of the NH2 terminus of ARHI significantly compromised its inhibitory activity, suggesting that this unique NH2-terminal extension contributes to ARHI's inhibition of STAT3-mediated transcriptional activity [13].
• Reactivation of the silenced and imprinted alleles of ARHI is associated with increased histone H3 acetylation and decreased histone H3 lysine 9 methylation [7].
• High levels of promoter methylation of the ARHI gene, encoding a RAS-related small G-protein, were strongly predictive of good survival in patients who had not received tamoxifen therapy [14].

Physical interactions of DIRAS3

• ARHI was found to interact with signal transducers and activators of transcription (STAT) 3, a latent transcription factor that transduces signals from the cell surface to the nucleus and activates gene transcription [13].
• Moreover, chromatin immunoprecipitation experiments revealed that both E2F1 and 4 bind to the ARHI promoter in breast cancer cells in vivo [3].

Other interactions of DIRAS3

• The expression of cyclin D1 and p21(WAF1/CIP1) was inversely correlated with that of ARHI [4].
• ARHI is a Ras-related small G-protein with a novel N-terminal extension that inhibits growth of ovarian and breast cancers [9].
• Two of them (CpG island I and II) are located within the promoter and adjacent exon 1 of the ARHI gene [15].
• Novel genes recently implicated in ovarian tumorigenesis are discussed, including NOEY2, OVCA1, and PIK3CA [16].

Analytical, diagnostic and therapeutic context of DIRAS3

• Consistent results were obtained with an in situ hybridization assay for ARHI at the mRNA level [4].
• Loss of ARHI expression is associated with tumor progression in breast cancer and decreased disease-free survival in ovarian cancer [8].
• Growth of ovarian and breast cancer xenografts is reversibly suppressed by ARHI, but expression of the NTD mutant produced only a limited inhibitory effect on growth of xenografts [8].
• When gene expression was analyzed on a custom cDNA array that contained 2304 known genes, infection with ARHI adenovirus up-regulated 15 genes relative to control cells infected with LacZ adenovirus [17].
• To this end, we first carried out radiation hybrid mapping of ARHI and surrounding markers, followed by a high-resolution study of loss of heterozygosity at 1p31 in 49 ovarian and breast cancers [12].

References