Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIKS3PC)

• DOT Name: Bromodomain-containing protein 8 (BRD8)
• Synonyms: Skeletal muscle abundant protein; Skeletal muscle abundant protein 2; Thyroid hormone receptor coactivating protein of 120 kDa; TrCP120; p120
• Gene Name: BRD8
• Related Disease:
  Adult glioblastoma
  Colon cancer
  Colon carcinoma
  Glioblastoma multiforme
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Adenocarcinoma
  Arteriosclerosis
  Atherosclerosis
  Burkitt lymphoma
  Capillary malformation-arteriovenous malformation syndrome
  Colorectal adenocarcinoma
  Colorectal carcinoma
  Ductal carcinoma
  Endometriosis
  Invasive ductal breast carcinoma
  Lung cancer
  Lung carcinoma
  Mucinous adenocarcinoma
  Oral cancer
  Oral cavity carcinoma
  Pancreatic cancer
  Prostate disease
  Squamous cell carcinoma
  Stroke
  Advanced cancer
  Colonic neoplasm
  Glioma
• UniProt ID: BRD8_HUMAN
• Pfam ID: PF00439
• Sequence:
  MATGTGKHKLLSTGPTEPWSIREKLCLASSVMRSGDQNWVSVSRAIKPFAEPGRPPDWFS
  QKHCASQYSELLETTETPKRKRGEKGEVVETVEDVIVRKLTAERVEELKKVIKETQERYR
  RLKRDAELIQAGHMDSRLDELCNDIATKKKLEEEEAEVKRKATDAAYQARQAVKTPPRRL
  PTVMVRSPIDSASPGGDYPLGDLTPTTMEEATSGVNESEMAVASGHLNSTGVLLEVGGVL
  PMIHGGEIQQTPNTVAASPAASGAPTLSRLLEAGPTQFTTPLASFTTVASEPPVKLVPPP
  VESVSQATIVMMPALPAPSSAPAVSTTESVAPVSQPDNCVPMEAVGDPHTVTVSMDSSEI
  SMIINSIKEECFRSGVAEAPVGSKAPSIDGKEELDLAEKMDIAVSYTGEELDFETVGDII
  AIIEDKVDDHPEVLDVAAVEAALSFCEENDDPQSLPGPWEHPIQQERDKPVPLPAPEMTV
  KQERLDFEETENKGIHELVDIREPSAEIKVEPAEPEPVISGAEIVAGVVPATSMEPPELR
  SQDLDEELGSTAAGEIVEADVAIGKGDETPLTNVKTEASPESMLSPSHGSNPIEDPLEAE
  TQHKFEMSDSLKEESGTIFGSQIKDAPGEDEEEDGVSEAASLEEPKEEDQGEGYLSEMDN
  EPPVSESDDGFSIHNATLQSHTLADSIPSSPASSQFSVCSEDQEAIQAQKIWKKAIMLVW
  RAAANHRYANVFLQPVTDDIAPGYHSIVQRPMDLSTIKKNIENGLIRSTAEFQRDIMLMF
  QNAVMYNSSDHDVYHMAVEMQRDVLEQIQQFLATQLIMQTSESGISAKSLRGRDSTRKQD
  ASEKDSVPMGSPAFLLSLFMGHEWVWLDSEQDHPNDSELSNDCRSLFSSWDSSLDLDVGN
  WRETEDPEAEELEESSPEREPSELLVGDGGSEESQEAARKASHQNLLHFLSEVAYLMEPL
  CISSNESSEGCCPPSGTRQEGREIKASEGERELCRETEELSAKGDPLVAEKPLGENGKPE
  VASAPSVICTVQGLLTESEEGEAQQESKGEDQGEVYVSEMEDQPPSGECDDAFNIKETPL
  VDTLFSHATSSKLTDLSQDDPVQDHLLFKKTLLPVWKMIASHRFSSPFLKPVSERQAPGY
  KDVVKRPMDLTSLKRNLSKGRIRTMAQFLRDLMLMFQNAVMYNDSDHHVYHMAVEMRQEV
  LEQIQVLNIWLDKRKGSSSLEGEPANPVDDGKPVF
• Function: May act as a coactivator during transcriptional activation by hormone-activated nuclear receptors (NR). Isoform 2 stimulates transcriptional activation by AR/DHTR, ESR1/NR3A1, RXRA/NR2B1 and THRB/ERBA2. At least isoform 1 and isoform 2 are components of the NuA4 histone acetyltransferase (HAT) complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A. This modification may both alter nucleosome - DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription. This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair. NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage. Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome.
• Tissue Specificity: Expressed in adipose tissue, brain, heart, kidney, liver, lung, pancreas, placenta and skeletal muscle.
• KEGG Pathway: ATP-dependent chromatin remodeling (hsa03082)
• Reactome Pathway: HATs acetylate histones (R-HSA-3214847)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Colon cancer	DISVC52G	Definitive	Altered Expression	[2]
Colon carcinoma	DISJYKUO	Definitive	Altered Expression	[2]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Neoplasm	DISZKGEW	Definitive	Biomarker	[3]
Prostate cancer	DISF190Y	Definitive	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[4]
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[5]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[6]
Burkitt lymphoma	DIS9D5XU	Strong	Biomarker	[7]
Capillary malformation-arteriovenous malformation syndrome	DISMN03Q	Strong	Genetic Variation	[8]
Colorectal adenocarcinoma	DISPQOUB	Strong	ModifyingMutation	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Ductal carcinoma	DIS15EA5	Strong	Biomarker	[11]
Endometriosis	DISX1AG8	Strong	Biomarker	[12]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[13]
Lung cancer	DISCM4YA	Strong	Altered Expression	[5]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[5]
Mucinous adenocarcinoma	DISKNFE8	Strong	Biomarker	[14]
Oral cancer	DISLD42D	Strong	Biomarker	[15]
Oral cavity carcinoma	DISZXMVL	Strong	Biomarker	[15]
Pancreatic cancer	DISJC981	Strong	Biomarker	[16]
Prostate disease	DISFVG19	Strong	Altered Expression	[17]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[5]
Stroke	DISX6UHX	Strong	Biomarker	[6]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[2]
Colonic neoplasm	DISSZ04P	Limited	Altered Expression	[9]
Glioma	DIS5RPEH	Limited	Biomarker	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Troglitazone	DM3VFPD	Approved	Bromodomain-containing protein 8 (BRD8) increases the response to substance of Troglitazone.	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Bromodomain-containing protein 8 (BRD8).	[19]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Bromodomain-containing protein 8 (BRD8).	[24]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Bromodomain-containing protein 8 (BRD8).	[28]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Bromodomain-containing protein 8 (BRD8).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Bromodomain-containing protein 8 (BRD8).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Bromodomain-containing protein 8 (BRD8).	[21]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Bromodomain-containing protein 8 (BRD8).	[22]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Bromodomain-containing protein 8 (BRD8).	[23]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Bromodomain-containing protein 8 (BRD8).	[25]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Bromodomain-containing protein 8 (BRD8).	[26]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Bromodomain-containing protein 8 (BRD8).	[25]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Bromodomain-containing protein 8 (BRD8).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Bromodomain-containing protein 8 (BRD8).	[30]

References

• [1] Interleukin-8 Secreted by Glioblastoma Cells Induces Microvascular Hyperpermeability Through NO Signaling Involving S-Nitrosylation of VE-Cadherin and p120 in Endothelial Cells.Front Physiol. 2019 Aug 8;10:988. doi: 10.3389/fphys.2019.00988. eCollection 2019.
• [2] miR-223 promotes colon cancer by directly targeting p120 catenin.Oncotarget. 2017 Jul 25;8(38):63764-63779. doi: 10.18632/oncotarget.19541. eCollection 2017 Sep 8.
• [3] A SMAP in the face for cancer.J Clin Invest. 2017 Jun 1;127(6):2048-2050. doi: 10.1172/JCI94763. Epub 2017 May 15.
• [4] MiR-185 attenuates androgen receptor function in prostate cancer indirectly by targeting bromodomain containing 8 isoform 2, an androgen receptor co-activator.Mol Cell Endocrinol. 2016 May 15;427:13-20. doi: 10.1016/j.mce.2016.02.023. Epub 2016 Mar 3.
• [5] Expression of nucleolar protein p120 in human lung cancer: difference in histological types as a marker for proliferation.Clin Cancer Res. 1997 Oct;3(10):1873-7.
• [6] p120 inhibits LPS/TNF-induced endothelial Ang2 synthesis and release in an NF-B independent fashion.Cytokine. 2019 Nov;123:154786. doi: 10.1016/j.cyto.2019.154786. Epub 2019 Jul 26.
• [7] Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers.J Biol Chem. 2020 Jan 17;295(3):757-770. doi: 10.1074/jbc.RA119.011443. Epub 2019 Dec 10.
• [8] RASA1 regulates the function of lymphatic vessel valves in mice.J Clin Invest. 2017 Jun 30;127(7):2569-2585. doi: 10.1172/JCI89607. Epub 2017 May 22.
• [9] BRD8 is a potential chemosensitizing target for spindle poisons in colorectal cancer therapy.Int J Oncol. 2009 Nov;35(5):1101-9. doi: 10.3892/ijo_00000425.
• [10] C20orf20 (MRG-binding protein) as a potential therapeutic target for colorectal cancer.Br J Cancer. 2010 Jan 19;102(2):325-31. doi: 10.1038/sj.bjc.6605500. Epub 2010 Jan 5.
• [11] Further evidence that E-cadherin is not a tumour suppressor gene in invasive ductal carcinoma of the breast: an immunohistochemical study.Histopathology. 2013 Apr;62(5):695-701. doi: 10.1111/his.12066. Epub 2013 Jan 24.
• [12] Nuclear receptor, coregulator signaling, and chromatin remodeling pathways suggest involvement of the epigenome in the steroid hormone response of endometrium and abnormalities in endometriosis.Reprod Sci. 2012 Feb;19(2):152-62. doi: 10.1177/1933719111415546. Epub 2011 Dec 2.
• [13] Correlation between E-cadherin and p120 expression in invasive ductal breast cancer with a lobular component and MRI findings.Virchows Arch. 2017 Dec;471(6):707-712. doi: 10.1007/s00428-017-2203-2. Epub 2017 Aug 4.
• [14] Invasive lobular carcinoma with extracellular mucin production and HER-2 overexpression: a case report and further case studies.Diagn Pathol. 2010 Jun 15;5:36. doi: 10.1186/1746-1596-5-36.
• [15] Nucleolar protein p120 expression in oral carcinoma.Anticancer Res. 1999 Mar-Apr;19(2B):1423-6.
• [16] Up-regulation, nuclear import, and tumor growth stimulation of the adhesion protein p120 in pancreatic cancer.Gastroenterology. 2003 Apr;124(4):949-60. doi: 10.1053/gast.2003.50142.
• [17] A novel splice variant of the nuclear coactivator p120 functions strongly for androgen receptor: characteristic expression in prostate disease.Endocr J. 2008 Aug;55(4):657-65. doi: 10.1507/endocrj.k07e-133. Epub 2008 Jun 18.
• [18] Expression of p120 nucleolar proliferating antigen in human gliomas and growth suppression of glioma cells by p120 ribozyme vector.Int J Oncol. 1999 Mar;14(3):417-24. doi: 10.3892/ijo.14.3.417.
• [19] 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.
• [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] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [22] 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.
• [23] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] 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.
• [29] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [30] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [31] Unliganded RXR acts as an inhibitory factor on troglitazone-induced activation. Life Sci. 2004 Dec 31;76(7):731-41. doi: 10.1016/j.lfs.2004.04.061.