Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMWB2P2)

• DOT Name: Fibrinogen silencer-binding protein (RAD54B)
• Gene Name: RAD54B
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Chromosomal disorder
  Colorectal carcinoma
  Isolated cleft lip
  Lymphoma
  Neoplasm
  Nijmegen breakage syndrome
  Polycystic ovarian syndrome
  Lung adenocarcinoma
  Adult lymphoma
  Carcinoma of liver and intrahepatic biliary tract
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Liver cancer
  Pediatric lymphoma
• UniProt ID: FSBP_HUMAN
• Pfam ID: PF13873
• Sequence:
  MVGKARSSNFTLSEKLDLLKLVKPYVKILEEHTNKHSVIVEKNRCWDIIAVNYNAIGVDR
  PPRTAQGLRTLYKRLKEYAKQELLQQKETQSDFKSNISEPTKKVMEMIPQISSFCLVRDR
  NHIQSANLDEEAQAGTSSLQVMLDHHPVAITVEVKQEEDIKPPPPLVLNSQQSDTLEQRE
  EHELVHVMERSLSPSLSSVDMRMTSSPSSIPRRDDFFRHESGEHFRSLLGYDPQILQMLK
  EEHQIILENQKNFGLYVQEKRDGLKRRQQLEEELLRAKIEVEKLKAIRLRHDLPEYNSL
• Function: Transcriptional repressor that down-regulates the expression of the fibrinogen gamma chain. Represses transcription of GSK3B gene promoter via its interaction with APBA1.
• Tissue Specificity: Expressed in multiple tissues including brain.

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Breast neoplasm	DISNGJLM	Strong	Genetic Variation	[3]
Chromosomal disorder	DISM5BB5	Strong	Genetic Variation	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[5]
Isolated cleft lip	DIS2O2JV	Strong	Genetic Variation	[6]
Lymphoma	DISN6V4S	Strong	Altered Expression	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Nijmegen breakage syndrome	DIS98HVL	Strong	Biomarker	[8]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[9]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[10]
Adult lymphoma	DISK8IZR	Limited	Altered Expression	[7]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[1]
Colon cancer	DISVC52G	Limited	Biomarker	[11]
Colon carcinoma	DISJYKUO	Limited	Biomarker	[11]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[1]
Liver cancer	DISDE4BI	Limited	Altered Expression	[1]
Pediatric lymphoma	DIS51BK2	Limited	Altered Expression	[7]

27 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 Fibrinogen silencer-binding protein (RAD54B).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Fibrinogen silencer-binding protein (RAD54B).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[18]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[19]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[20]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Fibrinogen silencer-binding protein (RAD54B).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Fibrinogen silencer-binding protein (RAD54B).	[22]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Fibrinogen silencer-binding protein (RAD54B).	[23]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[24]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[25]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[26]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[27]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[28]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Fibrinogen silencer-binding protein (RAD54B).	[29]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Fibrinogen silencer-binding protein (RAD54B).	[30]
GSK2110183	DMZHB37	Phase 2	GSK2110183 decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[31]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[33]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[35]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Fibrinogen silencer-binding protein (RAD54B).	[37]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[38]
geraniol	DMS3CBD	Investigative	geraniol decreases the expression of Fibrinogen silencer-binding protein (RAD54B).	[39]

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 decreases the methylation of Fibrinogen silencer-binding protein (RAD54B).	[32]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Fibrinogen silencer-binding protein (RAD54B).	[34]

References

• [1] Inhibition of RAD54B suppresses proliferation and promotes apoptosis in hepatoma cells.Oncol Rep. 2018 Sep;40(3):1233-1242. doi: 10.3892/or.2018.6522. Epub 2018 Jun 25.
• [2] RAD54B potentiates tumor growth and predicts poor prognosis of patients with luminal A breast cancer.Biomed Pharmacother. 2019 Oct;118:109341. doi: 10.1016/j.biopha.2019.109341. Epub 2019 Aug 21.
• [3] Loss of heterozygosity in the RAD54B region is not predictive for breast carcinomas.Pol J Pathol. 2007;58(1):3-6.
• [4] Rad54/Rad54B deficiency is associated to increased chromosome breakage in mouse spermatocytes.Mutagenesis. 2018 Oct 11;33(4):323-332. doi: 10.1093/mutage/gey027.
• [5] Specific synthetic lethal killing of RAD54B-deficient human colorectal cancer cells by FEN1 silencing.Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3276-81. doi: 10.1073/pnas.0813414106. Epub 2009 Feb 13.
• [6] Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity.Nat Commun. 2017 Feb 24;8:14364. doi: 10.1038/ncomms14364.
• [7] Mutations of a novel human RAD54 homologue, RAD54B, in primary cancer.Oncogene. 1999 Jun 3;18(22):3422-6. doi: 10.1038/sj.onc.1202691.
• [8] Nijmegen breakage syndrome gene (NBS1) is not the tumor suppressor gene at 8q21.3 involved in colorectal carcinoma.Oncol Rep. 2002 Jul-Aug;9(4):709-11.
• [9] Replication study of RAD54B and GREB1 polymorphisms and risk of PCOS in Han Chinese.Reprod Biomed Online. 2013 Sep;27(3):316-21. doi: 10.1016/j.rbmo.2013.05.007. Epub 2013 May 22.
• [10] Uncovering synthetic lethal interactions for therapeutic targets and predictive markers in lung adenocarcinoma.Oncotarget. 2016 Nov 8;7(45):73664-73680. doi: 10.18632/oncotarget.12046.
• [11] A role for RAD54B in homologous recombination in human cells.EMBO J. 2002 Jan 15;21(1-2):175-80. doi: 10.1093/emboj/21.1.175.
• [12] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [13] 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.
• [14] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [15] 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.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [20] 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.
• [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] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [23] 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.
• [24] Transcriptional profiling of MCF7 breast cancer cells in response to 5-Fluorouracil: relationship with cell cycle changes and apoptosis, and identification of novel targets of p53. Int J Cancer. 2006 Sep 1;119(5):1164-75.
• [25] Cannabidiol-induced transcriptomic changes and cellular senescence in human Sertoli cells. Toxicol Sci. 2023 Feb 17;191(2):227-238. doi: 10.1093/toxsci/kfac131.
• [26] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [27] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [28] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [29] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [30] 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.
• [31] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [32] 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.
• [33] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [34] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [35] 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.
• [36] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [37] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [38] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [39] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.