Details of Drug Off-Target (DOT)

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

• DOT Name: Rho-related GTP-binding protein RhoD (RHOD)
• Synonyms: Rho-related protein HP1; RhoHP1
• Gene Name: RHOD
• Related Disease:
  Hepatocellular carcinoma
  Non-insulin dependent diabetes
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  Congestive heart failure
  Gastric cancer
  High blood pressure
  Psoriatic arthritis
  Stomach cancer
  Chronic obstructive pulmonary disease
  OPTN-related open angle glaucoma
  Neoplasm
  Osteoarthritis
• UniProt ID: RHOD_HUMAN
• PDB ID: 2J1L; 7KDC
• Pfam ID: PF00071
• Sequence:
  MTAAQAAGEEAPPGVRSVKVVLVGDGGCGKTSLLMVFADGAFPESYTPTVFERYMVNLQV
  KGKPVHLHIWDTAGQDDYDRLRPLFYPDASVLLLCFDVTSPNSFDNIFNRWYPEVNHFCK
  KVPIIVVGCKTDLRKDKSLVNKLRRNGLEPVTYHRGQEMARSVGAVAYLECSARLHDNVH
  AVFQEAAEVALSSRGRNFWRRITQGFCVVT
• Function: Involved in endosome dynamics. May coordinate membrane transport with the function of the cytoskeleton. Involved in the internalization and trafficking of activated tyrosine kinase receptors such as PDGFRB. Participates in the reorganization of actin cytoskeleton; the function seems to involve WHAMM and includes regulation of filopodia formation and actin filament bundling. Can modulate the effect of DAPK3 in reorganization of actin cytoskeleton and focal adhesion dissolution.
• Tissue Specificity: Heart, placenta, liver, skeletal muscle, and pancreas and, with weaker intensity, in several other tissues.
• KEGG Pathway: Axon guidance (hsa04360)
• Reactome Pathway:
  RHOD GTPase cycle (R-HSA-9013405)
  RHO GTPases Activate Formins (R-HSA-5663220)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[1]
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Cardiovascular disease	DIS2IQDX	Strong	Altered Expression	[4]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[4]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[5]
High blood pressure	DISY2OHH	Strong	Altered Expression	[4]
Psoriatic arthritis	DISLWTG2	Strong	Altered Expression	[6]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[5]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Biomarker	[7]
OPTN-related open angle glaucoma	DISDR98A	Disputed	Genetic Variation	[8]
Neoplasm	DISZKGEW	Limited	Biomarker	[9]
Osteoarthritis	DIS05URM	Limited	Biomarker	[10]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Rho-related GTP-binding protein RhoD (RHOD) decreases the response to substance of Arsenic trioxide.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Rho-related GTP-binding protein RhoD (RHOD).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Rho-related GTP-binding protein RhoD (RHOD).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Rho-related GTP-binding protein RhoD (RHOD).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Rho-related GTP-binding protein RhoD (RHOD).	[11]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Rho-related GTP-binding protein RhoD (RHOD).	[14]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Rho-related GTP-binding protein RhoD (RHOD).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho-related GTP-binding protein RhoD (RHOD).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rho-related GTP-binding protein RhoD (RHOD).	[18]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Rho-related GTP-binding protein RhoD (RHOD).	[19]

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 increases the methylation of Rho-related GTP-binding protein RhoD (RHOD).	[16]

References

• [1] The diagnostic and prognostic role of RhoA in hepatocellular carcinoma.Aging (Albany NY). 2019 Jul 22;11(14):5158-5172. doi: 10.18632/aging.102110.
• [2] Investigation of the therapy targets of Yi-Qi-Yang-Yin-Hua-Tan-Qu-Yu recipe on type 2 diabetes by serum proteome labeled with iTRAQ.J Ethnopharmacol. 2018 Oct 5;224:1-14. doi: 10.1016/j.jep.2018.03.027. Epub 2018 Apr 11.
• [3] Coexpression of alpha6beta4 integrin and guanine nucleotide exchange factor Net1 identifies node-positive breast cancer patients at high risk for distant metastasis.Cancer Epidemiol Biomarkers Prev. 2009 Jan;18(1):80-6. doi: 10.1158/1055-9965.EPI-08-0842.
• [4] Pathophysiological effects of RhoA and Rho-associated kinase on cardiovascular system.J Hypertens. 2016 Jan;34(1):3-10. doi: 10.1097/HJH.0000000000000768.
• [5] Expressions of Ras Homolog Gene Family, Member A (RhoA) and Cyclooxygenase-2 (COX-2) Proteins in Early Gastric Cancer and Their Role in the Development of Gastric Cancer.Med Sci Monit. 2017 Jun 18;23:2979-2984. doi: 10.12659/msm.902367.
• [6] cMaf inducing protein inhibits cofilin? activity and alters podocyte cytoskeleton organization.Mol Med Rep. 2017 Oct;16(4):4955-4963. doi: 10.3892/mmr.2017.7156. Epub 2017 Aug 3.
• [7] Reduced nuclear translocation of serum response factor is associated with skeletal muscle atrophy in a cigarette smoke-induced mouse model of COPD.Int J Chron Obstruct Pulmon Dis. 2017 Feb 20;12:581-587. doi: 10.2147/COPD.S109243. eCollection 2017.
• [8] Toward Novel Diagnostics for Primary Open-Angle Glaucoma? An Association Study of Polymorphic Variation in Ras Homolog Family Member (A, B, C, D) Genes RHOA, RHOB, RHOC, and RHOD.OMICS. 2016 May;20(5):290-5. doi: 10.1089/omi.2016.0031.
• [9] Silencing RhoA inhibits migration and invasion through Wnt/-catenin pathway and growth through cell cycle regulation in human tongue cancer.Acta Biochim Biophys Sin (Shanghai). 2014 Aug;46(8):682-90. doi: 10.1093/abbs/gmu051.
• [10] RhoA/ROCK pathway: implication in osteoarthritis and therapeutic targets.Am J Transl Res. 2019 Sep 15;11(9):5324-5331. eCollection 2019.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] 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.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [15] Impact of epigallocatechin gallate on gene expression profiles of human hepatocellular carcinoma cell lines BEL7404/ADM and BEL7402/5-FU. Ai Zheng. 2008 Oct;27(10):1056-64.
• [16] 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.
• [17] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [18] 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.
• [19] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.
• [20] The NRF2-mediated oxidative stress response pathway is associated with tumor cell resistance to arsenic trioxide across the NCI-60 panel. BMC Med Genomics. 2010 Aug 13;3:37. doi: 10.1186/1755-8794-3-37.