Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPMJ39I)

• DOT Name: DNA-binding protein inhibitor ID-4 (ID4)
• Synonyms: Class B basic helix-loop-helix protein 27; bHLHb27; Inhibitor of DNA binding 4; Inhibitor of differentiation 4
• Gene Name: ID4
• Related Disease:
  Acute leukaemia
  Acute myelogenous leukaemia
  Adenocarcinoma
  Adult glioblastoma
  Aplastic anemia
  Astrocytoma
  Bladder cancer
  Brain neoplasm
  Breast carcinoma
  Breast neoplasm
  Burkitt lymphoma
  Castration-resistant prostate carcinoma
  Cervical cancer
  Cervical carcinoma
  Childhood myelodysplastic syndrome
  Glioblastoma multiforme
  Glioma
  Leukemia
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Myelodysplastic syndrome
  Non-hodgkin lymphoma
  Osteoporosis
  Ovarian cancer
  Ovarian neoplasm
  Psoriasis
  Skin disease
  Squamous cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Hepatocellular carcinoma
  Carcinoma
  Undifferentiated carcinoma
  Advanced cancer
  Breast cancer
  Cholestasis
  Colorectal carcinoma
  Colorectal neoplasm
  Gastric cancer
  Gastric neoplasm
  Hereditary diffuse gastric adenocarcinoma
  Lymphoma
  Melanoma
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Triple negative breast cancer
• UniProt ID: ID4_HUMAN
• Pfam ID: PF00010
• Sequence:
  MKAVSPVRPSGRKAPSGCGGGELALRCLAEHGHSLGGSAAAAAAAAAARCKAAEAAADEP
  ALCLQCDMNDCYSRLRRLVPTIPPNKKVSKVEILQHVIDYILDLQLALETHPALLRQPPP
  PAPPHHPAGTCPAAPPRTPLTALNTDPAGAVNKQGDSILCR
• Function: Transcriptional regulator (lacking a basic DNA binding domain) which negatively regulates the basic helix-loop-helix (bHLH) transcription factors by forming heterodimers and inhibiting their DNA binding and transcriptional activity. Implicated in regulating a variety of cellular processes, including cellular growth, senescence, differentiation, apoptosis, angiogenesis, and neoplastic transformation.
• KEGG Pathway:
  TGF-beta sig.ling pathway (hsa04350)
  Sig.ling pathways regulating pluripotency of stem cells (hsa04550)
• Reactome Pathway: NGF-stimulated transcription (R-HSA-9031628)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute leukaemia	DISDQFDI	Strong	Posttranslational Modification	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Posttranslational Modification	[2]
Adenocarcinoma	DIS3IHTY	Strong	Posttranslational Modification	[3]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[4]
Aplastic anemia	DISJRSC0	Strong	Posttranslational Modification	[5]
Astrocytoma	DISL3V18	Strong	Altered Expression	[4]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[6]
Brain neoplasm	DISY3EKS	Strong	Biomarker	[7]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[8]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[9]
Burkitt lymphoma	DIS9D5XU	Strong	Biomarker	[10]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Altered Expression	[11]
Cervical cancer	DISFSHPF	Strong	Biomarker	[12]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[12]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Posttranslational Modification	[1]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[13]
Glioma	DIS5RPEH	Strong	Biomarker	[14]
Leukemia	DISNAKFL	Strong	Biomarker	[15]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[16]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[16]
Myelodysplastic syndrome	DISYHNUI	Strong	Posttranslational Modification	[1]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[10]
Osteoporosis	DISF2JE0	Strong	Biomarker	[17]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[18]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[18]
Psoriasis	DIS59VMN	Strong	Posttranslational Modification	[19]
Skin disease	DISDW8R6	Strong	Biomarker	[19]
Squamous cell carcinoma	DISQVIFL	Strong	Posttranslational Modification	[19]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[6]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[6]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[20]
Carcinoma	DISH9F1N	Disputed	Biomarker	[21]
Undifferentiated carcinoma	DISIAZST	Disputed	Biomarker	[21]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[16]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[8]
Cholestasis	DISDJJWE	Limited	Biomarker	[22]
Colorectal carcinoma	DIS5PYL0	Limited	Posttranslational Modification	[23]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[24]
Gastric cancer	DISXGOUK	Limited	Biomarker	[25]
Gastric neoplasm	DISOKN4Y	Limited	Biomarker	[25]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Limited	Biomarker	[25]
Lymphoma	DISN6V4S	Limited	Altered Expression	[26]
Melanoma	DIS1RRCY	Limited	Biomarker	[27]
Neoplasm	DISZKGEW	Limited	Biomarker	[11]
Prostate cancer	DISF190Y	Limited	Altered Expression	[11]
Prostate carcinoma	DISMJPLE	Limited	Altered Expression	[11]
Triple negative breast cancer	DISAMG6N	Limited	Biomarker	[8]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	DNA-binding protein inhibitor ID-4 (ID4) affects the response to substance of Cisplatin.	[47]
Mitomycin	DMH0ZJE	Approved	DNA-binding protein inhibitor ID-4 (ID4) affects the response to substance of Mitomycin.	[47]

19 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 DNA-binding protein inhibitor ID-4 (ID4).	[28]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[30]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[31]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[32]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[25]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[34]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[35]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[36]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[37]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[38]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[39]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[40]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[41]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[36]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[43]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[44]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[45]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of DNA-binding protein inhibitor ID-4 (ID4).	[46]

1 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 DNA-binding protein inhibitor ID-4 (ID4).	[42]

References

• [1] Clinical implications of the quantitative detection of ID4 gene methylation in myelodysplastic syndrome.Eur J Med Res. 2015 Feb 20;20(1):16. doi: 10.1186/s40001-015-0092-x.
• [2] The diagnostic value of DNA methylation in leukemia: a systematic review and meta-analysis.PLoS One. 2014 May 8;9(5):e96822. doi: 10.1371/journal.pone.0096822. eCollection 2014.
• [3] Downregulation of ID4 by promoter hypermethylation in gastric adenocarcinoma.Oncogene. 2003 Oct 9;22(44):6946-53. doi: 10.1038/sj.onc.1206799.
• [4] Differential expression of ID4 and its association with TP53 mutation, SOX2, SOX4 and OCT-4 expression levels.PLoS One. 2013 Apr 16;8(4):e61605. doi: 10.1371/journal.pone.0061605. Print 2013.
• [5] Role of heteroplasmic mutations in the mitochondrial genome and the ID4 gene promoter methylation region in the pathogenesis of chronic aplastic anemia in patients suffering from Kidney yin deficiency.Chin J Integr Med. 2016 Jun;22(6):412-9. doi: 10.1007/s11655-014-1813-7. Epub 2015 Apr 29.
• [6] Amplification and overexpression of the ID4 gene at 6p22.3 in bladder cancer.Mol Cancer. 2005 May 5;4(1):16. doi: 10.1186/1476-4598-4-16.
• [7] Inhibitor of differentiation 4 drives brain tumor-initiating cell genesis through cyclin E and notch signaling.Genes Dev. 2008 Aug 1;22(15):2028-33. doi: 10.1101/gad.1668708.
• [8] Expression of ID4 protein in breast cancer cells induces reprogramming of tumour-associated macrophages.Breast Cancer Res. 2018 Jun 19;20(1):59. doi: 10.1186/s13058-018-0990-2.
• [9] Promoter methylation-associated loss of ID4 expression is a marker of tumour recurrence in human breast cancer.BMC Cancer. 2008 May 30;8:154. doi: 10.1186/1471-2407-8-154.
• [10] Inhibitor of DNA binding 4 functions as a tumor suppressor and is targetable by 5-aza-2'-deoxycytosine with potential therapeutic significance in Burkitt's lymphoma.Mol Med Rep. 2016 Feb;13(2):1269-74. doi: 10.3892/mmr.2015.4640. Epub 2015 Dec 4.
• [11] Inactivation of ID4 promotes a CRPC phenotype with constitutive AR activation through FKBP52.Mol Oncol. 2017 Apr;11(4):337-357. doi: 10.1002/1878-0261.12028. Epub 2017 Mar 2.
• [12] Exploration of the molecular mechanisms of cervical cancer based on mRNA expression profiles and predicted microRNA interactions.Oncol Lett. 2018 Jun;15(6):8965-8972. doi: 10.3892/ol.2018.8494. Epub 2018 Apr 13.
• [13] A cell-autonomous positive-signaling circuit associated with the PDGF-NO-ID4-regulatory axis in glioblastoma cells.Biochem Biophys Res Commun. 2017 Apr 29;486(2):564-570. doi: 10.1016/j.bbrc.2017.03.089. Epub 2017 Mar 19.
• [14] ID4 imparts chemoresistance and cancer stemness to glioma cells by derepressing miR-9*-mediated suppression of SOX2. Cancer Res. 2011 May 1;71(9):3410-21.
• [15] Global assessment of promoter methylation in a mouse model of cancer identifies ID4 as a putative tumor-suppressor gene in human leukemia.Nat Genet. 2005 Mar;37(3):265-74. doi: 10.1038/ng1521. Epub 2005 Feb 20.
• [16] Inhibitor of DNA-Binding Protein 4 Suppresses Cancer Metastasis through the Regulation of Epithelial Mesenchymal Transition in Lung Adenocarcinoma.Cancers (Basel). 2019 Dec 14;11(12):2021. doi: 10.3390/cancers11122021.
• [17] Id4, a new candidate gene for senile osteoporosis, acts as a molecular switch promoting osteoblast differentiation.PLoS Genet. 2010 Jul 8;6(7):e1001019. doi: 10.1371/journal.pgen.1001019.
• [18] Targeted tumor-penetrating siRNA nanocomplexes for credentialing the ovarian cancer oncogene ID4.Sci Transl Med. 2012 Aug 15;4(147):147ra112. doi: 10.1126/scitranslmed.3003778.
• [19] Parakeratosis in skin is associated with loss of inhibitor of differentiation 4 via promoter methylation.Hum Pathol. 2011 Dec;42(12):1878-87. doi: 10.1016/j.humpath.2011.02.005. Epub 2011 Jun 12.
• [20] Id4 promotes cell proliferation in hepatocellular carcinoma.Chin J Cancer. 2017 Feb 1;36(1):19. doi: 10.1186/s40880-017-0186-7.
• [21] Id4 regulates mammary epithelial cell growth and differentiation and is overexpressed in rat mammary gland carcinomas.Am J Pathol. 2003 Dec;163(6):2495-502. doi: 10.1016/S0002-9440(10)63604-8.
• [22] 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.
• [23] Epigenetic inactivation of ID4 in colorectal carcinomas correlates with poor differentiation and unfavorable prognosis.Clin Cancer Res. 2004 Nov 15;10(22):7475-83. doi: 10.1158/1078-0432.CCR-04-0689.
• [24] Cdc42 is highly expressed in colorectal adenocarcinoma and downregulates ID4 through an epigenetic mechanism.Int J Oncol. 2008 Jul;33(1):185-93.
• [25] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [26] Frequent DNA methylation but not mutation of the ID4 gene in malignant lymphoma.J Clin Exp Hematop. 2007 Apr;47(1):15-8. doi: 10.3960/jslrt.47.15.
• [27] Inhibitor of DNA Binding 4 (ID4) is highly expressed in human melanoma tissues and may function to restrict normal differentiation of melanoma cells.PLoS One. 2015 Feb 2;10(2):e0116839. doi: 10.1371/journal.pone.0116839. eCollection 2015.
• [28] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [29] 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.
• [30] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [31] 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.
• [32] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [33] Chemical genomic screening for methylation-silenced genes in gastric cancer cell lines using 5-aza-2'-deoxycytidine treatment and oligonucleotide microarray. Cancer Sci. 2006 Jan;97(1):64-71.
• [34] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [35] Unique transcriptome, pathways, and networks in the human endometrial fibroblast response to progesterone in endometriosis. Biol Reprod. 2011 Apr;84(4):801-15.
• [36] 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.
• [37] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [38] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [39] 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.
• [40] Non-redundant inhibitor of differentiation (Id) gene expression and function in human prostate epithelial cells. Prostate. 2006 Jun 15;66(9):921-35. doi: 10.1002/pros.20366.
• [41] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [42] 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.
• [43] 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.
• [44] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [45] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [46] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [47] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.