Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTROVLJ0)

• DOT Name: Polycomb complex protein BMI-1 (BMI1)
• Synonyms: Polycomb group RING finger protein 4; RING finger protein 51
• Gene Name: BMI1
• UniProt ID: BMI1_HUMAN
• PDB ID: 2H0D; 2NA1; 3RPG; 4R8P; 5FR6; 6WI7; 6WI8; 7ND1
• Pfam ID: PF16207 ; PF13923
• Sequence:
  MHRTTRIKITELNPHLMCVLCGGYFIDATTIIECLHSFCKTCIVRYLETSKYCPICDVQV
  HKTRPLLNIRSDKTLQDIVYKLVPGLFKNEMKRRRDFYAAHPSADAANGSNEDRGEVADE
  DKRIITDDEIISLSIEFFDQNRLDRKVNKDKEKSKEEVNDKRYLRCPAAMTVMHLRKFLR
  SKMDIPNTFQIDVMYEEEPLKDYYTLMDIAYIYTWRRNGPLPLKYRVRPTCKRMKISHQR
  DGLTNAGELESDSGSDKANSPAGGIPSTSSCLPSPSTPVQSPHPQFPHISSTMNGTSNSP
  SGNHQSSFANRPRKSSVNGSSATSSG
• Function: Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. The complex composed of RNF2, UB2D3 and BMI1 binds nucleosomes, and has activity only with nucleosomal histone H2A. In the PRC1-like complex, regulates the E3 ubiquitin-protein ligase activity of RNF2/RING2.
• KEGG Pathway:
  Polycomb repressive complex (hsa03083)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
  Transcriptio.l misregulation in cancer (hsa05202)
  MicroR.s in cancer (hsa05206)
• Reactome Pathway:
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of transcription cofactors (R-HSA-3899300)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  SUMOylation of RNA binding proteins (R-HSA-4570464)
  SUMOylation of DNA methylation proteins (R-HSA-4655427)
  RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known (R-HSA-8939243)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  Oxidative Stress Induced Senescence (R-HSA-2559580)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic trioxide	DM61TA4	Approved	Polycomb complex protein BMI-1 (BMI1) decreases the response to substance of Arsenic trioxide.	[18]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	Polycomb complex protein BMI-1 (BMI1) decreases the response to substance of phorbol 12-myristate 13-acetate.	[18]
Butanoic acid	DMTAJP7	Investigative	Polycomb complex protein BMI-1 (BMI1) decreases the response to substance of Butanoic acid.	[18]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Glutathione	DMAHMT9	Approved	Polycomb complex protein BMI-1 (BMI1) increases the abundance of Glutathione.	[19]

2 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 Polycomb complex protein BMI-1 (BMI1).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Polycomb complex protein BMI-1 (BMI1).	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Polycomb complex protein BMI-1 (BMI1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Polycomb complex protein BMI-1 (BMI1).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Polycomb complex protein BMI-1 (BMI1).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Polycomb complex protein BMI-1 (BMI1).	[5]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Polycomb complex protein BMI-1 (BMI1).	[7]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Polycomb complex protein BMI-1 (BMI1).	[8]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Polycomb complex protein BMI-1 (BMI1).	[9]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Polycomb complex protein BMI-1 (BMI1).	[10]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Polycomb complex protein BMI-1 (BMI1).	[11]
Melatonin	DMKWFBT	Approved	Melatonin increases the expression of Polycomb complex protein BMI-1 (BMI1).	[12]
Ibrutinib	DMHZCPO	Approved	Ibrutinib decreases the expression of Polycomb complex protein BMI-1 (BMI1).	[13]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Polycomb complex protein BMI-1 (BMI1).	[14]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Polycomb complex protein BMI-1 (BMI1).	[13]
BETULINIC ACID	DMBUI2A	Phase 1	BETULINIC ACID decreases the expression of Polycomb complex protein BMI-1 (BMI1).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Polycomb complex protein BMI-1 (BMI1).	[15]
MG-132	DMKA2YS	Preclinical	MG-132 increases the expression of Polycomb complex protein BMI-1 (BMI1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Polycomb complex protein BMI-1 (BMI1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Polycomb complex protein BMI-1 (BMI1).	[17]

References

• [1] 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.
• [2] 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.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] Bisphenol A promotes human prostate stem-progenitor cell self-renewal and increases in vivo carcinogenesis in human prostate epithelium. Endocrinology. 2014 Mar;155(3):805-17. doi: 10.1210/en.2013-1955. Epub 2014 Jan 1.
• [6] 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.
• [7] 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.
• [8] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [9] Rosiglitazone impairs proliferation of human adrenocortical cancer: preclinical study in a xenograft mouse model. Endocr Relat Cancer. 2010 Feb 18;17(1):169-77. doi: 10.1677/ERC-09-0170. Print 2010 Mar.
• [10] Enhancement of cancer stem-like and epithelial-mesenchymal transdifferentiation property in oral epithelial cells with long-term nicotine exposure: reversal by targeting SNAIL. Toxicol Appl Pharmacol. 2013 Feb 1;266(3):459-69.
• [11] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [12] Neuronal Bmi-1 is critical for melatonin induced ubiquitination and proteasomal degradation of -synuclein in experimental Parkinson's disease models. Neuropharmacology. 2021 Aug 15;194:108372. doi: 10.1016/j.neuropharm.2020.108372. Epub 2020 Nov 4.
• [13] Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib. Blood. 2015 Sep 24;126(13):1565-74.
• [14] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
• [15] 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.
• [16] Environmental-relevant bisphenol A exposure promotes ovarian cancer stemness by regulating microRNA biogenesis. J Cell Mol Med. 2023 Sep;27(18):2792-2803. doi: 10.1111/jcmm.17920. Epub 2023 Aug 23.
• [17] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [18] BMI1 reprogrammes histone acetylation and enhances c-fos pathway via directly binding to Zmym3 in malignant myeloid progression. J Cell Mol Med. 2014 Jun;18(6):1004-17. doi: 10.1111/jcmm.12246. Epub 2014 Feb 27.
• [19] Enhancing chemotherapy response with Bmi-1 silencing in ovarian cancer. PLoS One. 2011 Mar 21;6(3):e17918. doi: 10.1371/journal.pone.0017918.