Genomic structure and promoter characterization of an imprinted tumor suppressor gene ARHI

Luo, Robert Z.; Peng, Hao; Xu, Fengji; Bao, Jiaju; Pang, Yong; Pershad, Rashmi; Issa, Jean–Pierre J.; Liao, Warren S.L.; Bast, Robert C.; Yu, Yinhua

doi:10.1016/s0167-4781(01)00226-3

Cited by 40 publications

(35 citation statements)

References 26 publications

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“…CpG island I is located about 1 kb upstream of the transcription start site, CpG island II spans both the transcription start site and a portion of exon 1 and CpG island III is located within the protein coding region of exon 2. 6 A study on breast cancer cells suggested CpG island II as the functionally most relevant site for epigenetic inactivation. 7 DIRAS3 maps to 1p31, a chromosomal region that often exhibits loss of heterozygosity in oligodendroglial tumors of the brain.…”

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confidence: 99%

Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss

Riemenschneider

Reifenberger

2008

Intl Journal of Cancer

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Deletion of the short arm of chromosome 1 is common in oligodendroglial tumors and has been identified as a powerful molecular marker for response to radio-and chemotherapy as well as favorable prognosis. Here, we investigated a series of 59 human primary gliomas for aberrations of the DIRAS3 (ARHI) gene, a maternally imprinted RAS-related tumor suppressor at 1p31. We found that DIRAS3 mRNA expression levels were significantly decreased in oligodendrogliomas with 1p deletion when compared to tumors with retention on 1p. While mutational analysis yielded no tumor-associated mutations, assessment of the methylation status of DIRAS3 showed biallelic DIRAS3 inactivation due to methylation of the retained allele in 95% of oligodendrogliomas (19 out of 20) with 1p deletions. In contrast, only 28% of oligodendrogliomas (5 out of 18) without 1p deletions and less than 5% of astrocytic tumors (1 out 21) had biallelic inactivation, i.e., methylation of both DIRAS3 alleles. Furthermore, in oligodendroglioma patients biallelic DIRAS3 inactivation was significantly associated with low DIRAS3 transcripts levels and longer overall survival. Taken together, our data suggest DIRAS3 as a novel, prognostically relevant candidate gene that is frequently methylated and silenced in oligodendroglial tumors with 1p deletion. ' 2008 Wiley-Liss, Inc.Key words: DIRAS3; ARHI; oligodendroglioma; 1p; methylation The DIRAS3 gene at 1p31 encodes a small 26 kDa GTPase with 60% homology to Ras and Rap. 1 Despite its affiliation to the RAS superfamily DIRAS3 exhibits characteristics of a tumor suppressor gene. In breast cancer cell lines the expression of DIRAS3 suppresses clonogenic growth, reduces invasiveness and induces apoptosis. 2 The downstream mechanisms conveying these tumor suppressor functions of DIRAS3 have not yet been fully understood. Inhibition of signalling through RAS/MAPK, PI3K and STAT3 pathways, downregulation of cyclin D1, upregulation of p21(WAF1/CIP1) as well as induction of JNK and caspase-independent, calpain-dependent apoptosis have all been attributed to mediate DIRAS3 downstream signaling effects. [2][3][4][5] DIRAS3 is one of about 40 known imprinted genes within the genome. In human tissues, it is solely expressed from the paternal allele, while the maternal copy is silenced early in embryonal development. 1 The gene comprises 2 exons with the entire 229-base pair coding region located in exon 2. Three potential CpG islands have been attributed to DIRAS3. CpG island I is located about 1 kb upstream of the transcription start site, CpG island II spans both the transcription start site and a portion of exon 1 and CpG island III is located within the protein coding region of exon 2. 6 A study on breast cancer cells suggested CpG island II as the functionally most relevant site for epigenetic inactivation. 7 DIRAS3 maps to 1p31, a chromosomal region that often exhibits loss of heterozygosity in oligodendroglial tumors of the brain. 8 In oligodendrogliomas, determination of the 1p deletion status has attracted particula...

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confidence: 99%

Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss

Riemenschneider

Reifenberger

2008

Intl Journal of Cancer

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“…In addition, ARHI contains a unique 34 amino acid extension at its N-terminus and exhibits high affinity for GTP despite having low intrinsic GTPase activity (6). Structural differences also support the observation that ARHI remains the only tumor suppressor gene identified in the Ras superfamily to date (18). Characterization of ARHI activity has included the following observations; in a study by Hu et al (19), ARHI was shown to mediate downregulation of the NF-κB signaling pathway, thereby acting as a tumor suppressor protein in pancreatic cancer cells.…”

Section: Discussionmentioning

confidence: 56%

Breast cancer cells are arrested at different phases of the cell cycle following the re-expression of ARHI

et al. 2014

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Abstract. ARHI is a maternally imprinted tumor suppressor gene that is expressed in normal breast epithelial cells but not in most breast cancer cells. Aberrant methylation and hypernomic histone deacetylation have been implicated in the silencing of ARHI. To investigate the mechanism of ARHI induction, MDA-MB-231 breast cancer cells were either transfected with the eukaryotic expression vector, pcDNA3.1(+)-ARHI, or were simultaneously treated with a histone deacetylase inhibitor, [trichostatin A, (TSA)] and the methyltransferase inhibitor, 5-aza-2'-deoxycytidine (DAC). The latter treatment group also included the targeting of ARHI by small interfering RNA (siRNA) to further examine interactions between ARHI and the drugs applied. Levels of ARHI were detected by western blotting, MTT assays were used to evaluate cell proliferation, and both cell cycle progression and apoptosis were detected using flow cytometry. Both the transfection of pcDNA3.1(+)-ARHI and the application of TSA+DAC induced the expression of ARHI. Furthermore, reduced cell proliferation, cell cycle arrest and enhanced apoptosis were observed for both groups compared to controls. However, a G1/S cell cycle arrest was observed for the pcDNA3.1(+)-ARHI group, while a G2 cell cycle arrest was observed for the TSA+DAC group. The latter effect was reversed with the introduction of ARHI-targeted siRNA in combination with TSA+DAC treatment. To further clarify these observations, expression levels of several key cell cycle regulators were analyzed by western blotting. The pcDNA3.1(+)-ARHI group exhibited higher expression levels of p53, p21 and p27, and lower levels of cyclin D1, CDK4 and CDK6 when compared to the control group (P<0.05). For the TSA+DAC group, higher levels of p53, p21, cyclin B1 and Chk1 were detected, concomitant with lower levels of CDK1, when compared to the control group. Taken together, these results suggest that ARHI acts as a tumor suppressor gene in MDA-MB-231 cells and, although TSA+DAC can block the cells at different cell cycle phage, the antitumor effect is ARHI-dependent.

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“…However, due to its special feature of being a maternally imprinted gene, loss or down-regulation of the paternal allele's expression can lead to the unlimited cell growth, which may contribute to tumorigenesis in certain cancers (3)(4)(5)(6). Previous studies have showed that ARHI loss or down-regulation could be caused by loss of heterozygosity (7) and/or epigenetic events such as DNA methylation, histone methylation and histone acetylation (9,10,15). However, ARHI expression and its function have not been studied in prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

“…ARHI is also down-regulated by epigenetic mechanisms like DNA methylation, histone methylation and histone acetalyation (8,9). It has also been reported that ARHI is down-regulated by binding of transcription factor E2F to the ARHI promoter region (10,11). This kind of negative regulation can be reversed by TSA treatment, E2F binding site mutation and E2F siRNA (11).…”

Section: Introductionmentioning

confidence: 99%

542 Micrornas 221/222 and Genistein Mediated Regulation of Arhi Tumor Suppressor Gene in Prostate Cancer

Chen¹,

Deng²,

Majid³

et al. 2010

Journal of Urology

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Genomic structure and promoter characterization of an imprinted tumor suppressor gene ARHI

Cited by 40 publications

References 26 publications

Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss

Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p loss

Breast cancer cells are arrested at different phases of the cell cycle following the re-expression of ARHI

542 Micrornas 221/222 and Genistein Mediated Regulation of Arhi Tumor Suppressor Gene in Prostate Cancer

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