Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTGE8K45)

• DOT Name: Rho-related BTB domain-containing protein 1 (RHOBTB1)
• Gene Name: RHOBTB1
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colon cancer
  Colon carcinoma
  Head and neck cancer
  Head and neck carcinoma
  High blood pressure
  Juvenile idiopathic arthritis
  Neoplasm
  Non-insulin dependent diabetes
  Prostate cancer
  Prostate carcinoma
  Squamous cell carcinoma
  Cutaneous squamous cell carcinoma
• UniProt ID: RHBT1_HUMAN
• Pfam ID: PF00651 ; PF00071
• Sequence:
  MDADMDYERPNVETIKCVVVGDNAVGKTRLICARACNTTLTQYQLLATHVPTVWAIDQYR
  VCQEVLERSRDVVDEVSVSLRLWDTFGDHHKDRRFAYGRSDVVVLCFSIANPNSLNHVKS
  MWYPEIKHFCPRTPVILVGCQLDLRYADLEAVNRARRPLARPIKRGDILPPEKGREVAKE
  LGLPYYETSVFDQFGIKDVFDNAIRAALISRRHLQFWKSHLKKVQKPLLQAPFLPPKAPP
  PVIKIPECPSMGTNEAACLLDNPLCADVLFILQDQEHIFAHRIYLATSSSKFYDLFLMEC
  EESPNGSEGACEKEKQSRDFQGRILSVDPEEEREEGPPRIPQADQWKSSNKSLVEALGLE
  AEGAVPETQTLTGWSKGFIGMHREMQVNPISKRMGPMTVVRMDASVQPGPFRTLLQFLYT
  GQLDEKEKDLVGLAQIAEVLEMFDLRMMVENIMNKEAFMNQEITKAFHVRKANRIKECLS
  KGTFSDVTFKLDDGAISAHKPLLICSCEWMAAMFGGSFVESANSEVYLPNINKISMQAVL
  DYLYTKQLSPNLDLDPLELIALANRFCLPHLVALAEQHAVQELTKAATSGVGIDGEVLSY
  LELAQFHNAHQLAAWCLHHICTNYNSVCSKFRKEIKSKSADNQEYFERHRWPPVWYLKEE
  DHYQRVKREREKEDIALNKHRSRRKWCFWNSSPAVA
• Tissue Specificity: Ubiquitous, with highest levels in skeletal muscle, placenta, testis, stomach, and kidney, followed by uterus and adrenal gland. Expressed in a variety of fetal tissues.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway: RHOBTB1 GTPase cycle (R-HSA-9013422)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Colon cancer	DISVC52G	Strong	Biomarker	[3]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[3]
Head and neck cancer	DISBPSQZ	Strong	Genetic Variation	[4]
Head and neck carcinoma	DISOU1DS	Strong	Genetic Variation	[4]
High blood pressure	DISY2OHH	Strong	Biomarker	[5]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[7]
Prostate cancer	DISF190Y	Strong	Biomarker	[1]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[1]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[4]
Cutaneous squamous cell carcinoma	DIS3LXUG	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[11]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[13]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[16]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[17]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[18]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[19]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[20]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[21]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[22]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[24]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[27]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Rho-related BTB domain-containing protein 1 (RHOBTB1).	[28]

References

• [1] RhoBTB1 interacts with ROCKs and inhibits invasion.Biochem J. 2019 Sep 13;476(17):2499-2514. doi: 10.1042/BCJ20190203.
• [2] The tumor suppressor RhoBTB1 controls Golgi integrity and breast cancer cell invasion through METTL7B.BMC Cancer. 2017 Feb 20;17(1):145. doi: 10.1186/s12885-017-3138-3.
• [3] The tumor suppressor gene RhoBTB1 is a novel target of miR-31 in human colon cancer.Int J Oncol. 2013 Feb;42(2):676-82. doi: 10.3892/ijo.2012.1746. Epub 2012 Dec 20.
• [4] Identification of a candidate tumor suppressor gene RHOBTB1 located at a novel allelic loss region 10q21 in head and neck cancer.J Cancer Res Clin Oncol. 2006 Jan;132(1):19-27. doi: 10.1007/s00432-005-0033-0. Epub 2005 Sep 17.
• [5] PPAR and RhoBTB1 in hypertension.Curr Opin Nephrol Hypertens. 2020 Mar;29(2):161-170. doi: 10.1097/MNH.0000000000000579.
• [6] Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.Arthritis Rheum. 2009 Jul;60(7):2113-23. doi: 10.1002/art.24534.
• [7] Genetic Variants in HSD17B3, SMAD3, and IPO11 Impact Circulating Lipids in Response to Fenofibrate in Individuals With Type 2 Diabetes.Clin Pharmacol Ther. 2018 Apr;103(4):712-721. doi: 10.1002/cpt.798. Epub 2017 Nov 3.
• [8] MicroRNA-31 functions as an oncogenic microRNA in cutaneous squamous cell carcinoma cells by targeting RhoTBT1.Oncol Lett. 2017 Mar;13(3):1078-1082. doi: 10.3892/ol.2017.5554. Epub 2017 Jan 2.
• [9] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [10] 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.
• [11] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [14] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [15] 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.
• [16] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [17] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [18] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [19] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [22] 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.
• [23] Regulation of aryl hydrocarbon receptor function by selective estrogen receptor modulators. Mol Endocrinol. 2010 Jan;24(1):33-46.
• [24] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [25] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [26] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [27] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [28] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.