Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR6NHI2)

• DOT Name: Cbp/p300-interacting transactivator 4 (CITED4)
• Synonyms: MSG1-related protein 2; MRG-2
• Gene Name: CITED4
• Related Disease:
  Glioma
  Astrocytoma
  Breast cancer
  Breast carcinoma
  Breast lobular carcinoma
  Breast neoplasm
  Colorectal carcinoma
  Glioblastoma multiforme
  Myocardial infarction
  Oral cavity squamous cell carcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Neoplasm
• UniProt ID: CITE4_HUMAN
• Pfam ID: PF04487
• Sequence:
  MADHLMLAEGYRLVQRPPSAAAAHGPHALRTLPPYAGPGLDSGLRPRGAPLGPPPPRQPG
  ALAYGAFGPPSSFQPFPAVPPPAAGIAHLQPVATPYPGRAAAPPNAPGGPPGPQPAPSAA
  APPPPAHALGGMDAELIDEEALTSLELELGLHRVRELPELFLGQSEFDCFSDLGSAPPAG
  SVSC
• Function: Acts as a transcriptional coactivator for TFAP2/AP-2. Enhances estrogen-dependent transactivation mediated by estrogen receptors. May function as an inhibitor of transactivation by HIF1A by disrupting HIF1A interaction with CREBBP. May be involved in regulation of gene expression during development and differentiation of blood cells, endothelial cells and mammary epithelial cells.
• Tissue Specificity: Expressed in most tissues examined with highest levels of expression in heart, liver, skeletal muscle and pancreas. Also expressed in bladder cell line ECV-304 and in various breast cancer cell lines. Also detected in both in situ and invasive breast tumors where its expression is down-regulated and mostly restricted to the cytoplasm of malignant epithelium. Down-regulation of expression is associated with elevated levels of HIF1A and increased tumor growth and angiogenesis.
• Reactome Pathway: Activation of the TFAP2 (AP-2) family of transcription factors (R-HSA-8866907)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Glioma	DIS5RPEH	Definitive	Altered Expression	[1]
Astrocytoma	DISL3V18	Strong	Genetic Variation	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Posttranslational Modification	[3]
Breast lobular carcinoma	DISBY98Q	Strong	Posttranslational Modification	[3]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Genetic Variation	[2]
Myocardial infarction	DIS655KI	Strong	Biomarker	[5]
Oral cavity squamous cell carcinoma	DISQVJVA	Strong	Altered Expression	[6]
Lung cancer	DISCM4YA	Limited	Biomarker	[7]
Lung carcinoma	DISTR26C	Limited	Biomarker	[7]
Lung neoplasm	DISVARNB	Limited	Altered Expression	[7]
Neoplasm	DISZKGEW	Limited	Altered Expression	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[11]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[13]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[15]
Melphalan	DMOLNHF	Approved	Melphalan increases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[17]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[20]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[21]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[22]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[23]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Cbp/p300-interacting transactivator 4 (CITED4).	[24]

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 Cbp/p300-interacting transactivator 4 (CITED4).	[19]

References

• [1] Hypermethylation and transcriptional downregulation of the CITED4 gene at 1p34.2 in oligodendroglial tumours with allelic losses on 1p and 19q.Oncogene. 2007 Jul 26;26(34):5010-6. doi: 10.1038/sj.onc.1210297. Epub 2007 Feb 19.
• [2] Mutational analysis of the CITED4 gene in glioblastomas.Cancer Genet Cytogenet. 2008 Sep;185(2):114-6. doi: 10.1016/j.cancergencyto.2008.05.013.
• [3] Aberrant DNA methylation but not mutation of CITED4 is associated with alteration of HIF-regulated genes in breast cancer.Breast Cancer Res Treat. 2011 Nov;130(1):319-29. doi: 10.1007/s10549-011-1657-1. Epub 2011 Jul 14.
• [4] CITED4 gene silencing in colorectal cancer cells modulates adherens/tight junction gene expression and reduces cell proliferation.J Cancer Res Clin Oncol. 2016 Jan;142(1):225-37. doi: 10.1007/s00432-015-2011-5. Epub 2015 Aug 5.
• [5] High-intensity interval training increase GATA4, CITED4 and c-Kit and decreases C/EBP in rats after myocardial infarction.Life Sci. 2019 Mar 15;221:319-326. doi: 10.1016/j.lfs.2019.02.045. Epub 2019 Feb 22.
• [6] Characterization of Copy Number Variations in Oral Cavity Squamous Cell Carcinoma Reveals a Novel Role for MLLT3 in Cell Invasiveness.Oncologist. 2019 Dec;24(12):e1388-e1400. doi: 10.1634/theoncologist.2019-0063. Epub 2019 Jul 4.
• [7] A targetable HB-EGF-CITED4 axis controls oncogenesis in lung cancer.Oncogene. 2017 May 25;36(21):2946-2956. doi: 10.1038/onc.2016.465. Epub 2017 Jan 16.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [13] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [14] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [15] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [16] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] 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.
• [19] 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.
• [20] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [21] 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.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [24] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.