Atlas of Genetics and Cytogenetics

in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS

Gene Section Review

DIRAS3 (DIRAS family, GTP -binding RAS -like 3) Yinhua Yu, Zhen Lu, Robert Z Luo, Robert C Bast Jr The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 354, Houston, TX 77030, USA (YY, ZL, RZL, RCBJr)

Published in Atlas Database: September 2009 Online updated version : http://AtlasGeneticsOncology.org/Genes/DIRAS3ID702ch1p31.html DOI: 10.4267/2042/44814 This article is an update of : Guénard F, Durocher F. DHX9 (DEAH (Asp-Glu-Ala-His) box polypeptide 9). Atlas Genet Cytogenet Oncol Haematol 2010;14(6):547-549

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2010 Atlas of Genetics and Cytogenetics in Oncology and Haematology

region consisting of 81 nucleotides, whereas the second Identity exon contains the entire protein-coding region. The two Other names: ARHI; NOEY2; RHOI exons are separated by an intron of 3.2 kb. There are HGNC (Hugo): DIRAS3 three CpG island regions. CPG island I (nucleotide (nt) -1232 to -914) is located about 1 kb upstream of the Location: 1p31.3 transcription initiation site; CpG island II (nt -206 to Local order: Telomeric to GNG12, RMU7-80P and +79) is near the transcription initiation region and centromeric to GPR177, RPS7P4. adjacent exon 1; CpG island III (nt +3343 to +3691) is Note: DIRAS3 is also known as NOEY2 and ARHI located in the protein-encoding region of exon 2. (Ras homologue member I). Transcription DNA/RNA The entire protein-coding region is located within exon 2 and encodes a 229-residue small GTP-binding Description protein. DIRAS3 encompasses a 7.2-kb region and includes 2.0 kb of the 5'- flanking region, two exons, an intron, and Pseudogene a 1.2-kb 3'-flanking region. No known pseudogenes. The first exon contains only the 5'-noncoding

The DIRAS3 gene contains two exons interrupted by a large intron. The red-blocked and opened boxes represent the coding and non- coding regions, respectively. There are three CpG island regions. Blue: CPG island I; green: CpG island II; grey: CpG island III.

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 714 DIRAS3 (DIRAS family, GTP-binding RAS-like 3) Yu Y, et al.

DIRAS3 protein.

Protein Implicated in Description Solid cancers DIRAS3 encodes a 26-kDa GTPase. The DIRAS3 gene Disease ORF contains three motifs typical of Ras/Rap family Ovarian cancer, breast cancer, pancreatic cancer, members: (1) a highly conserved GTP binding domain, hepatocellular carcinoma, oligodendroglial tumor, (2) a putative effector domain YLPTIENTY, and (3) follicular thyroid cancer. the membrane localizing CAAX motif at the COOH Prognosis terminus. DIRAS3 contains a unique 34 amino-acid Loss of DIRAS3 expression is associated with tumor extension at the N-terminus and differs from other progression in breast cancer and decreased disease-free members of Ras-superfamily. survival in ovarian cancer. Expression Oncogenesis DIRAS3 is expressed in brain, heart, liver, lung, DIRAS3 is monoallelically expressed and maternally pancreas, breast and ovary. imprinted, expression from the paternal allele of Localisation DIRAS3 can be lost through LOH, CpG methylation, and transcriptional regulation. DIRAS3 is DIRAS is associated at the cell membrane through its downregulated in 60% of ovarian and breast cancers: prenylation at the C-terminal cysteine residue. LOH was found in 40% of ovarian and breast cancers. Mutation of the conserved CAAX box at the C- Mutations have not been detected, but the remaining terminus led to a loss of its membrane association. allele is silenced in ovarian cancer and breast cancer by Function methylation in approximately 10-15% of cases. In the remaining cancers, DIRAS3 is downregulated by DIRAS3 is a maternally imprinted tumor suppressor transcriptional mechanisms that involve E2F1 and gene that belongs to the Ras superfamily of small G E2F4, as well as by the loss of RNA binding proteins proteins. DIRAS3 regulates cell cycle, motility, that decrease the half-life of DIRAS3 mRNA. angiogenesis, autophagy and tumor dormancy. Introduction of this gene into cancer cells that lack DIRAS3 expression inhibits proliferation and motility References of cancer cells. DIRAS3 truncates signaling through the Yu Y, Xu F, Peng H, Fang X, Zhao S, Li Y, Cuevas B, Kuo WL, Ras/MAP pathway, induces p21WAF1/CIP1 , down- Gray JW, Siciliano M, Mills GB, Bast RC Jr. NOEY2 (ARHI), an imprinted putative tumor suppressor gene in ovarian and regulates cyclin D1, and triggers apoptosis. DIRAS3 is breast carcinomas. Proc Natl Acad Sci U S A. 1999 Jan required for autophagy and that re-expression of 5;96(1):214-9 DIRAS3 protein in ovarian cancer cells will induce Peng H, Xu F, Pershad R, Hunt KK, Frazier ML, Berchuck A, autophagic cell death in culture. In xenografts, re- Gray JW, Hogg D, Bast RC Jr, Yu Y. ARHI is the center of expression of DIRAS3 also induces autophagy, but can allelic deletion on chromosome 1p31 in ovarian and breast also promote tumor dormancy in the presence of factors cancers. Int J Cancer. 2000 Jun 1;86(5):690-4 that promote survival in the cancer microenvironment. Xu F, Xia W, Luo RZ, Peng H, Zhao S, Dai J, Long Y, Zou L, Le W, Liu J, Parlow AF, Hung MC, Bast RC Jr, Yu Y. The Homology human ARHI tumor suppressor gene inhibits lactation and DIRAS3 shares 56% amino acid homology with growth in transgenic mice. Cancer Res. 2000 Sep 1;60(17):4913-20 Rap1A, 56% with Rap1B, 58% with Rap 2A, 62% with Rap2B, 59% with K-Ras, and 54% with H-Ras. Luo RZ, Peng H, Xu F, Bao J, Pang Y, Pershad R, Issa JP, Liao WS, Bast RC Jr, Yu Y. Genomic structure and promoter DIRAS3 shares about 40% homology with DIRAS1 characterization of an imprinted tumor suppressor gene ARHI. and DIRAS2. Biochim Biophys Acta. 2001 Jun 28;1519(3):216-22 Bao JJ, Le XF, Wang RY, Yuan J, Wang L, Atkinson EN, Mutations LaPushin R, Andreeff M, Fang B, Yu Y, Bast RC Jr. Reexpression of the tumor suppressor gene ARHI induces Note apoptosis in ovarian and breast cancer cells through a Mutations have not been detected. caspase-independent calpain-dependent pathway. Cancer Res. 2002 Dec 15;62(24):7264-72

Atlas Genet Cytogenet Oncol Haematol. 2010; 14(8) 715 DIRAS3 (DIRAS family, GTP-binding RAS-like 3) Yu Y, et al.

Fujii S, Luo RZ, Yuan J, Kadota M, Oshimura M, Dent SR, the tumor suppressor gene ARHI in breast cancer. Oncogene. Kondo Y, Issa JP, Bast RC Jr, Yu Y. Reactivation of the 2006 Jan 12;25(2):230-9 silenced and imprinted alleles of ARHI is associated with increased histone H3 acetylation and decreased histone H3 Lu Z, Luo RZ, Peng H, Rosen DG, Atkinson EN, Warneke C, lysine 9 methylation. Hum Mol Genet. 2003 Aug Huang M, Nishmoto A, Liu J, Liao WS, Yu Y, Bast RC Jr. 1;12(15):1791-800 Transcriptional and posttranscriptional down-regulation of the imprinted tumor suppressor gene ARHI (DRAS3) in ovarian Luo RZ, Fang X, Marquez R, Liu SY, Mills GB, Liao WS, Yu Y, cancer. Clin Cancer Res. 2006 Apr 15;12(8):2404-13 Bast RC. ARHI is a Ras-related small G-protein with a novel N- terminal extension that inhibits growth of ovarian and breast Yu Y, Luo R, Lu Z, Wei Feng W, Badgwell D, Issa JP, Rosen cancers. Oncogene. 2003 May 15;22(19):2897-909 DG, Liu J, Bast RC Jr. Biochemistry and biology of ARHI (DIRAS3), an imprinted tumor suppressor gene whose Wang L, Hoque A, Luo RZ, Yuan J, Lu Z, Nishimoto A, Liu J, expression is lost in ovarian and breast cancers. Methods Sahin AA, Lippman SM, Bast RC Jr, Yu Y. Loss of the Enzymol. 2006;407:455-68 expression of the tumor suppressor gene ARHI is associated with progression of breast cancer. Clin Cancer Res. 2003 Sep Feng W, Lu Z, Luo RZ, Zhang X, Seto E, Liao WS, Yu Y. 1;9(10 Pt 1):3660-6 Multiple histone deacetylases repress tumor suppressor gene ARHI in breast cancer. Int J Cancer. 2007 Apr 15;120(8):1664- Yu Y, Fujii S, Yuan J, Luo RZ, Wang L, Bao J, Kadota M, 8 Oshimura M, Dent SR, Issa JP, Bast RC Jr. Epigenetic regulation of ARHI in breast and ovarian cancer cells. Ann N Y Lu Z, Luo RZ, Lu Y, Zhang X, Yu Q, Khare S, Kondo S, Kondo Acad Sci. 2003 Mar;983:268-77 Y, Yu Y, Mills GB, Liao WS, Bast RC Jr. The tumor suppressor gene ARHI regulates autophagy and tumor dormancy in Yuan J, Luo RZ, Fujii S, Wang L, Hu W, Andreeff M, Pan Y, human ovarian cancer cells. J Clin Invest. 2008 Kadota M, Oshimura M, Sahin AA, Issa JP, Bast RC Jr, Yu Y. Dec;118(12):3917-29 Aberrant methylation and silencing of ARHI, an imprinted tumor suppressor gene in which the function is lost in breast Riemenschneider MJ, Reifenberger J, Reifenberger G. cancers. Cancer Res. 2003 Jul 15;63(14):4174-80 Frequent biallelic inactivation and transcriptional silencing of the DIRAS3 gene at 1p31 in oligodendroglial tumors with 1p Rosen DG, Wang L, Jain AN, Lu KH, Luo RZ, Yu Y, Liu J, Bast loss. Int J Cancer. 2008 Jun 1;122(11):2503-10 RC Jr. Expression of the tumor suppressor gene ARHI in epithelial ovarian cancer is associated with increased Huang J, Lin Y, Li L, Qing D, Teng XM, Zhang YL, Hu X, Hu Y, expression of p21WAF1/CIP1 and prolonged progression-free Yang P, Han ZG. ARHI, as a novel suppressor of cell growth survival. Clin Cancer Res. 2004 Oct 1;10(19):6559-66 and downregulated in human hepatocellular carcinoma, could contribute to hepatocarcinogenesis. Mol Carcinog. 2009 Nishimoto A, Yu Y, Lu Z, Mao X, Ren Z, Watowich SS, Mills Feb;48(2):130-40 GB, Liao WS, Chen X, Bast RC Jr, Luo RZ. A Ras homologue member I directly inhibits signal transducers and activators of Huang S, Chang IS, Lin W, Ye W, Luo RZ, Lu Z, Lu Y, Zhang transcription 3 translocation and activity in human breast and K, Liao WS, Tao T, Bast RC Jr, Chen X, Yu Y. ARHI (DIRAS3), ovarian cancer cells. Cancer Res. 2005 Aug 1;65(15):6701-10 an imprinted tumour suppressor gene, binds to importins and blocks nuclear import of cargo proteins. Biosci Rep. 2009 Dec Weber F, Aldred MA, Morrison CD, Plass C, Frilling A, 15;30(3):159-68 Broelsch CE, Waite KA, Eng C. Silencing of the maternally imprinted tumor suppressor ARHI contributes to follicular This article should be referenced as such: thyroid carcinogenesis. J Clin Endocrinol Metab. 2005 Feb;90(2):1149-55 Yu Y, Lu Z, Luo RZ, Bast RC Jr. DIRAS3 (DIRAS family, GTP- binding RAS-like 3). Atlas Genet Cytogenet Oncol Haematol. Lu Z, Luo RZ, Peng H, Huang M, Nishmoto A, Hunt KK, Helin 2010; 14(8):714-716. K, Liao WS, Yu Y. E2F-HDAC complexes negatively regulate

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