Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2DATFX)

• DOT Name: Rho-related BTB domain-containing protein 2 (RHOBTB2)
• Synonyms: Deleted in breast cancer 2 gene protein; p83
• Gene Name: RHOBTB2
• Related Disease:
  Bladder cancer
  Complex neurodevelopmental disorder
  Urinary bladder neoplasm
  Advanced cancer
  Arthritis
  Bone cancer
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Developmental and epileptic encephalopathy, 64
  Epilepsy
  Gastric cancer
  Gastric neoplasm
  Head-neck squamous cell carcinoma
  Intellectual disability
  Intervertebral disc degeneration
  Lung cancer
  Lyme disease
  Movement disorder
  Neoplasm
  Neurodevelopmental disorder
  Osteosarcoma
  Renal cell carcinoma
  Stomach cancer
  Hereditary breast carcinoma
  Carcinoma
  Invasive ductal breast carcinoma
  Peripheral neuropathy
  Plasma cell myeloma
  Urinary bladder cancer
• UniProt ID: RHBT2_HUMAN
• Pfam ID: PF00651 ; PF00071
• Sequence:
  MDSDMDYERPNVETIKCVVVGDNAVGKTRLICARACNATLTQYQLLATHVPTVWAIDQYR
  VCQEVLERSRDVVDDVSVSLRLWDTFGDHHKDRRFAYGRSDVVVLCFSIANPNSLHHVKT
  MWYPEIKHFCPRAPVILVGCQLDLRYADLEAVNRARRPLARPIKPNEILPPEKGREVAKE
  LGIPYYETSVVAQFGIKDVFDNAIRAALISRRHLQFWKSHLRNVQRPLLQAPFLPPKPPP
  PIIVVPDPPSSSEECPAHLLEDPLCADVILVLQERVRIFAHKIYLSTSSSKFYDLFLMDL
  SEGELGGPSEPGGTHPEDHQGHSDQHHHHHHHHHGRDFLLRAASFDVCESVDEAGGSGPA
  GLRASTSDGILRGNGTGYLPGRGRVLSSWSRAFVSIQEEMAEDPLTYKSRLMVVVKMDSS
  IQPGPFRAVLKYLYTGELDENERDLMHIAHIAELLEVFDLRMMVANILNNEAFMNQEITK
  AFHVRRTNRVKECLAKGTFSDVTFILDDGTISAHKPLLISSCDWMAAMFGGPFVESSTRE
  VVFPYTSKSCMRAVLEYLYTGMFTSSPDLDDMKLIILANRLCLPHLVALTEQYTVTGLME
  ATQMMVDIDGDVLVFLELAQFHCAYQLADWCLHHICTNYNNVCRKFPRDMKAMSPENQEY
  FEKHRWPPVWYLKEEDHYQRARKEREKEDYLHLKRQPKRRWLFWNSPSSPSSSAASSSSP
  SSSSAVV
• Tissue Specificity: Ubiquitous, with highest levels in neural tissues. Expression is also detected in fetal lung, heart, and brain.
• KEGG Pathway: Ubiquitin mediated proteolysis (hsa04120)
• Reactome Pathway: RHOBTB2 GTPase cycle (R-HSA-9013418)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Definitive	Posttranslational Modification	[1]
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[2]
Urinary bladder neoplasm	DIS7HACE	Definitive	Posttranslational Modification	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Arthritis	DIST1YEL	Strong	Biomarker	[4]
Bone cancer	DIS38NA0	Strong	Biomarker	[5]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Posttranslational Modification	[7]
Developmental and epileptic encephalopathy, 64	DISF0VGU	Strong	Autosomal dominant	[8]
Epilepsy	DISBB28L	Strong	Genetic Variation	[9]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[10]
Gastric neoplasm	DISOKN4Y	Strong	Genetic Variation	[10]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[11]
Intellectual disability	DISMBNXP	Strong	Biomarker	[8]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[12]
Lung cancer	DISCM4YA	Strong	Genetic Variation	[11]
Lyme disease	DISO70G5	Strong	Biomarker	[4]
Movement disorder	DISOJJ2D	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Biomarker	[6]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[8]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[13]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[10]
Hereditary breast carcinoma	DISAEZT5	moderate	Genetic Variation	[14]
Carcinoma	DISH9F1N	Limited	Altered Expression	[15]
Invasive ductal breast carcinoma	DIS43J58	Limited	Biomarker	[15]
Peripheral neuropathy	DIS7KN5G	Limited	Genetic Variation	[16]
Plasma cell myeloma	DIS0DFZ0	Limited	Altered Expression	[16]
Urinary bladder cancer	DISDV4T7	Limited	Posttranslational Modification	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bortezomib	DMNO38U	Approved	Rho-related BTB domain-containing protein 2 (RHOBTB2) increases the response to substance of Bortezomib.	[16]

8 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 Rho-related BTB domain-containing protein 2 (RHOBTB2).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Rho-related BTB domain-containing protein 2 (RHOBTB2).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Rho-related BTB domain-containing protein 2 (RHOBTB2).	[21]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Rho-related BTB domain-containing protein 2 (RHOBTB2).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Rho-related BTB domain-containing protein 2 (RHOBTB2).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Rho-related BTB domain-containing protein 2 (RHOBTB2).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Rho-related BTB domain-containing protein 2 (RHOBTB2).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Rho-related BTB domain-containing protein 2 (RHOBTB2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of Rho-related BTB domain-containing protein 2 (RHOBTB2).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Rho-related BTB domain-containing protein 2 (RHOBTB2).	[25]

References

• [1] DBC2 gene is silenced by promoter methylation in bladder cancer.Urol Oncol. 2008 Sep-Oct;26(5):465-9. doi: 10.1016/j.urolonc.2007.08.009. Epub 2008 Jul 21.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] RhoBTB2 (DBC2) functions as tumor suppressor via inhibiting proliferation, preventing colony formation and inducing apoptosis in breast cancer cells.Gene. 2011 Oct 15;486(1-2):74-80. doi: 10.1016/j.gene.2011.07.018. Epub 2011 Jul 23.
• [4] Establishment of enzyme-linked immunosorbent assay using purified recombinant 83-kilodalton antigen of Borrelia burgdorferi sensu stricto and Borrelia afzelii for serodiagnosis of Lyme disease.J Clin Microbiol. 1995 Oct;33(10):2596-600. doi: 10.1128/jcm.33.10.2596-2600.1995.
• [5] Downregulated RhoBTB2 expression contributes to poor outcome in osteosarcoma patients.Cancer Biother Radiopharm. 2013 Dec;28(10):709-16. doi: 10.1089/cbr.2012.1386. Epub 2013 Jun 18.
• [6] DBC2/RhoBTB2 functions as a tumor suppressor protein via Musashi-2 ubiquitination in breast cancer.Oncogene. 2017 May 18;36(20):2802-2812. doi: 10.1038/onc.2016.441. Epub 2016 Dec 12.
• [7] Decreased expression of the DBC2 gene and its clinicopathological significance in breast cancer: correlation with aberrant DNA methylation.Biotechnol Lett. 2013 Aug;35(8):1175-81. doi: 10.1007/s10529-013-1190-x. Epub 2013 Apr 2.
• [8] Identification of novel genetic causes of Rett syndrome-like phenotypes. J Med Genet. 2016 Mar;53(3):190-9. doi: 10.1136/jmedgenet-2015-103568. Epub 2016 Jan 6.
• [9] Missense Variants in RHOBTB2 Cause a Developmental and Epileptic Encephalopathy in Humans, and Altered Levels Cause Neurological Defects in Drosophila.Am J Hum Genet. 2018 Jan 4;102(1):44-57. doi: 10.1016/j.ajhg.2017.11.008. Epub 2017 Dec 21.
• [10] Genetic analysis of the DBC2 gene in gastric cancer.Acta Oncol. 2008;47(3):366-71. doi: 10.1080/02841860701644094. Epub 2007 Sep 28.
• [11] The atypical Rho GTPase RhoBTB2 is required for expression of the chemokine CXCL14 in normal and cancerous epithelial cells.Oncogene. 2008 Nov 20;27(54):6856-65. doi: 10.1038/onc.2008.317. Epub 2008 Sep 1.
• [12] Genes associated with disc degeneration identified using microarray gene expression profiling and bioinformatics analysis.Genet Mol Res. 2013 Apr 26;12(2):1431-9. doi: 10.4238/2013.April.26.5.
• [13] Genome-wide association study identifies multiple risk loci for renal cell carcinoma.Nat Commun. 2017 Jun 9;8:15724. doi: 10.1038/ncomms15724.
• [14] Mutation analysis of the DBC2 gene in sporadic and familial breast cancer.Acta Oncol. 2007;46(6):770-2. doi: 10.1080/02841860601047752.
• [15] A novel tumor suppressor gene RhoBTB2 (DBC2): frequent loss of expression in sporadic breast cancer.Mol Carcinog. 2010 Mar;49(3):283-9. doi: 10.1002/mc.20598.
• [16] Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. doi: 10.1016/S1470-2045(10)70206-0. Epub 2010 Sep 21.
• [17] RhoBTB2 gene in breast cancer is silenced by promoter methylation.Int J Mol Med. 2014 Mar;33(3):722-8. doi: 10.3892/ijmm.2013.1593. Epub 2013 Dec 18.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [20] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [21] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [25] 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.
• [26] 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.
• [27] Epigenetic influences of low-dose bisphenol A in primary human breast epithelial cells. Toxicol Appl Pharmacol. 2010 Oct 15;248(2):111-21.
• [28] Mechanisms of peripheral neuropathy associated with bortezomib and vincristine in patients with newly diagnosed multiple myeloma: a prospective analysis of data from the HOVON-65/GMMG-HD4 trial. Lancet Oncol. 2010 Nov;11(11):1057-65. doi: 10.1016/S1470-2045(10)70206-0. Epub 2010 Sep 21.