Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3XHLQA)

• DOT Name: GTP-binding protein Di-Ras3 (DIRAS3)
• Synonyms: Distinct subgroup of the Ras family member 3; Rho-related GTP-binding protein RhoI
• Gene Name: DIRAS3
• Related Disease:
  Ovarian cancer
  Adult glioblastoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Epithelial ovarian cancer
  Exanthem
  Glioblastoma multiforme
  Glioma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Oligospermia
  Ovarian neoplasm
  Pheochromocytoma
  Prostate cancer
  Prostate carcinoma
  Bone osteosarcoma
  Carcinoma of liver and intrahepatic biliary tract
  Gastric cancer
  Hepatocellular carcinoma
  Liver cancer
  Osteosarcoma
  Stomach cancer
  Breast neoplasm
  Ductal breast carcinoma in situ
  Thyroid gland follicular carcinoma
• UniProt ID: DIRA3_HUMAN
• PDB ID: 6NAZ
• Pfam ID: PF00071
• Sequence:
  MGNASFGSKEQKLLKRLRLLPALLILRAFKPHRKIRDYRVVVVGTAGVGKSTLLHKWASG
  NFRHEYLPTIENTYCQLLGCSHGVLSLHITDSKSGDGNRALQRHVIARGHAFVLVYSVTK
  KETLEELKAFYELICKIKGNNLHKFPIVLVGNKSDDTHREVALNDGATCAMEWNCAFMEI
  SAKTDVNVQELFHMLLNYKKKPTTGLQEPEKKSQMPNTTEKLLDKCIIM
• Tissue Specificity: Expressed in normal ovarian and breast epithelial cells but not in ovarian and breast cancers.

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ovarian cancer	DISZJHAP	Definitive	Altered Expression	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[4]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[1]
Exanthem	DISAFOQN	Strong	Altered Expression	[5]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Altered Expression	[6]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Oligospermia	DIS6YJF3	Strong	Biomarker	[7]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[1]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[10]
Bone osteosarcoma	DIST1004	moderate	Altered Expression	[11]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Altered Expression	[12]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[13]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[14]
Liver cancer	DISDE4BI	moderate	Altered Expression	[12]
Osteosarcoma	DISLQ7E2	moderate	Altered Expression	[11]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[13]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[15]
Ductal breast carcinoma in situ	DISLCJY7	Limited	Altered Expression	[15]
Thyroid gland follicular carcinoma	DISFK2QT	Limited	Biomarker	[16]

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[19]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[22]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[23]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[24]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[29]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[30]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of GTP-binding protein Di-Ras3 (DIRAS3).	[31]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of GTP-binding protein Di-Ras3 (DIRAS3).	[26]

References

• [1] The role of vascular endothelial growth factor, interleukin 8, and insulinlike growth factor in sustaining autophagic DIRAS3-induced dormant ovarian cancer xenografts.Cancer. 2019 Apr 15;125(8):1267-1280. doi: 10.1002/cncr.31935. Epub 2019 Jan 8.
• [2] Oncogenic Ras is downregulated by ARHI and induces autophagy by Ras/AKT/mTOR pathway in glioblastoma.BMC Cancer. 2019 May 14;19(1):441. doi: 10.1186/s12885-019-5643-z.
• [3] DIRAS3-Derived Peptide Inhibits Autophagy in Ovarian Cancer Cells by Binding to Beclin1.Cancers (Basel). 2019 Apr 18;11(4):557. doi: 10.3390/cancers11040557.
• [4] Breast cancer cells are arrested at different phases of the cell cycle following the re-expression of ARHI.Oncol Rep. 2014 May;31(5):2358-64. doi: 10.3892/or.2014.3107. Epub 2014 Mar 21.
• [5] NOEY2 mutations in primary breast cancers and breast hyperplasia.Breast. 2009 Jun;18(3):197-203. doi: 10.1016/j.breast.2009.04.004. Epub 2009 May 30.
• [6] Effect of ARHI on lung cancer cell proliferation, apoptosis and invasion in vitro.Mol Biol Rep. 2013 Mar;40(3):2671-8. doi: 10.1007/s11033-012-2353-x. Epub 2012 Dec 18.
• [7] Idiopathic male infertility is strongly associated with aberrant DNA methylation of imprinted loci in sperm: a case-control study.Clin Epigenetics. 2018 Oct 29;10(1):134. doi: 10.1186/s13148-018-0568-y.
• [8] ARHI is a novel epigenetic silenced tumor suppressor in sporadic pheochromocytoma.Oncotarget. 2017 Sep 21;8(49):86325-86338. doi: 10.18632/oncotarget.21149. eCollection 2017 Oct 17.
• [9] Oncogenic DIRAS3 promotes malignant phenotypes of glioma by activating EGFR-AKT signaling.Biochem Biophys Res Commun. 2018 Oct 28;505(2):413-418. doi: 10.1016/j.bbrc.2018.09.119. Epub 2018 Sep 25.
• [10] MicroRNAs 221/222 and genistein-mediated regulation of ARHI tumor suppressor gene in prostate cancer.Cancer Prev Res (Phila). 2011 Jan;4(1):76-86. doi: 10.1158/1940-6207.CAPR-10-0167. Epub 2010 Nov 11.
• [11] Zebularine enhances apoptosis of human osteosarcoma cells by suppressing methylation of ARHI.Cancer Sci. 2016 Dec;107(12):1851-1857. doi: 10.1111/cas.13088. Epub 2016 Dec 19.
• [12] ARHI, as a novel suppressor of cell growth and downregulated in human hepatocellular carcinoma, could contribute to hepatocarcinogenesis.Mol Carcinog. 2009 Feb;48(2):130-40. doi: 10.1002/mc.20461.
• [13] Distinct subgroup of the Ras family member 3 (DIRAS3) expression impairs metastasis and induces autophagy of gastric cancer cells in mice.J Cancer Res Clin Oncol. 2018 Oct;144(10):1869-1886. doi: 10.1007/s00432-018-2708-3. Epub 2018 Jul 24.
• [14] Computational discovery of niclosamide ethanolamine, a repurposed drug candidate that reduces growth of hepatocellular carcinoma cells initro and in mice by inhibiting cell division cycle 37 signaling. Gastroenterology. 2017 Jun;152(8):2022-2036.
• [15] Re-expression of ARHI (DIRAS3) induces autophagy in breast cancer cells and enhances the inhibitory effect of paclitaxel.BMC Cancer. 2011 Jan 19;11:22. doi: 10.1186/1471-2407-11-22.
• [16] Silencing of the maternally imprinted tumor suppressor ARHI contributes to follicular thyroid carcinogenesis.J Clin Endocrinol Metab. 2005 Feb;90(2):1149-55. doi: 10.1210/jc.2004-1447. Epub 2004 Nov 16.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [19] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [20] Comparative Analysis of Transcriptomic Changes including mRNA and microRNA Expression Induced by the Xenoestrogens Zearalenone and Bisphenol A in Human Ovarian Cells. Toxins (Basel). 2023 Feb 9;15(2):140. doi: 10.3390/toxins15020140.
• [21] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [22] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [23] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [24] Cardiac toxicity from ethanol exposure in human-induced pluripotent stem cell-derived cardiomyocytes. Toxicol Sci. 2019 May 1;169(1):280-292.
• [25] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [26] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [27] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [28] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [29] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [30] MCM-2 is a therapeutic target of Trichostatin A in colon cancer cells. Toxicol Lett. 2013 Jul 31;221(1):23-30. doi: 10.1016/j.toxlet.2013.05.643. Epub 2013 Jun 13.
• [31] Early gene response in lithium chloride induced apoptosis. Apoptosis. 2005 Jan;10(1):75-90. doi: 10.1007/s10495-005-6063-x.