Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTERIAD4)

• DOT Name: Rho-related GTP-binding protein RhoU (RHOU)
• Synonyms: CDC42-like GTPase 1; GTP-binding protein-like 1; Rho GTPase-like protein ARHU; Ryu GTPase; Wnt-1 responsive Cdc42 homolog 1; WRCH-1
• Gene Name: RHOU
• Related Disease:
  Small lymphocytic lymphoma
  Advanced cancer
  Breast neoplasm
  Cardiac failure
  Congestive heart failure
  Dilated cardiomyopathy 1A
  Kidney neoplasm
  Malignant uterine tumour
  Plasma cell myeloma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: RHOU_HUMAN
• PDB ID: 2Q3H
• Pfam ID: PF00071
• Sequence:
  MPPQQGDPAFPDRCEAPPVPPRRERGGRGGRGPGEPGGRGRAGGAEGRGVKCVLVGDGAV
  GKTSLVVSYTTNGYPTEYIPTAFDNFSAVVSVDGRPVRLQLCDTAGQDEFDKLRPLCYTN
  TDIFLLCFSVVSPSSFQNVSEKWVPEIRCHCPKAPIILVGTQSDLREDVKVLIELDKCKE
  KPVPEEAAKLCAEEIKAASYIECSALTQKNLKEVFDAAIVAGIQYSDTQQQPKKSKSRTP
  DKMKNLSKSWWKKYCCFV
• Function: Acts upstream of PAK1 to regulate the actin cytoskeleton, adhesion turnover and increase cell migration. Stimulates quiescent cells to reenter the cell cycle. Has no detectable GTPase activity but its high intrinsic guanine nucleotide exchange activity suggests it is constitutively GTP-bound. Plays a role in the regulation of cell morphology and cytoskeletal organization. Required in the control of cell shape.
• Tissue Specificity: Ubiquitously expressed in all tissues examined. Expressed at high levels in the stomach, small intestine, brain, skeletal muscle and placenta.
• Reactome Pathway:
  RHOU GTPase cycle (R-HSA-9013420)
  Interleukin-4 and Interleukin-13 signaling (R-HSA-6785807)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Small lymphocytic lymphoma	DIS30POX	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Cardiac failure	DISDC067	Strong	Altered Expression	[3]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[3]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[4]
Kidney neoplasm	DISBNZTN	Strong	Altered Expression	[2]
Malignant uterine tumour	DIS3QDT8	Strong	Altered Expression	[2]
Plasma cell myeloma	DIS0DFZ0	moderate	Altered Expression	[5]
Prostate cancer	DISF190Y	Disputed	Altered Expression	[6]
Prostate carcinoma	DISMJPLE	Disputed	Altered Expression	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[10]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Rho-related GTP-binding protein RhoU (RHOU).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[14]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Rho-related GTP-binding protein RhoU (RHOU).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[16]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[17]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Rho-related GTP-binding protein RhoU (RHOU).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[19]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[20]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[21]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[22]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[22]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene decreases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[27]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Rho-related GTP-binding protein RhoU (RHOU).	[28]

2 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 increases the methylation of Rho-related GTP-binding protein RhoU (RHOU).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Rho-related GTP-binding protein RhoU (RHOU).	[25]

References

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• [2] Expression of WRCH1 in human cancer and down-regulation of WRCH1 by beta-estradiol in MCF-7 cells.Int J Oncol. 2002 Apr;20(4):777-83.
• [3] RNA-sequencing analysis reveals new alterations in cardiomyocyte cytoskeletal genes in patients with heart failure.Lab Invest. 2014 Jun;94(6):645-53. doi: 10.1038/labinvest.2014.54. Epub 2014 Apr 7.
• [4] Functional networks of nucleocytoplasmic transport-related genes differentiate ischemic and dilated cardiomyopathies. A new therapeutic opportunity.PLoS One. 2014 Aug 19;9(8):e104709. doi: 10.1371/journal.pone.0104709. eCollection 2014.
• [5] The small GTPase RhoU lays downstream of JAK/STAT signaling and mediates cell migration in multiple myeloma.Blood Cancer J. 2018 Feb 13;8(2):20. doi: 10.1038/s41408-018-0053-z.
• [6] Validation of Novel Biomarkers for Prostate Cancer Progression by the Combination of Bioinformatics, Clinical and Functional Studies.PLoS One. 2016 May 19;11(5):e0155901. doi: 10.1371/journal.pone.0155901. eCollection 2016.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [12] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [13] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [14] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [15] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [16] 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.
• [17] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [18] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [19] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [20] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [21] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [22] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [23] Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid. Haematologica. 2007 Jan;92(1):115-20.
• [24] 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.
• [25] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [26] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [27] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [28] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.