Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0AAXAC)

• DOT Name: Cell division cycle-associated protein 4 (CDCA4)
• Synonyms: Hematopoietic progenitor protein
• Gene Name: CDCA4
• Related Disease:
  Breast cancer
  Breast carcinoma
  Triple negative breast cancer
  Melanoma
• UniProt ID: CDCA4_HUMAN
• Pfam ID: PF06031
• Sequence:
  MFARGLKRKCVGHEEDVEGALAGLKTVSSYSLQRQSLLDMSLVKLQLCHMLVEPNLCRSV
  LIANTVRQIQEEMTQDGTWRTVAPQAAERAPLDRLVSTEILCRAAWGQEGAHPAPGLGDG
  HTQGPVSDLCPVTSAQAPRHLQSSAWEMDGPRENRGSFHKSLDQIFETLETKNPSCMEEL
  FSDVDSPYYDLDTVLTGMMGGARPGPCEGLEGLAPATPGPSSSCKSDLGELDHVVEILVE
  T
• Function: May participate in the regulation of cell proliferation through the E2F/RB pathway. May be involved in molecular regulation of hematopoietic stem cells and progenitor cell lineage commitment and differentiation.
• Tissue Specificity: Highest levels of expression in the pancreas, thymus, testis, spleen, liver, placenta and leukocytes. Relatively low levels in the lung, kidney, prostate, ovary, small intestine and colon. Hardly detectable, if at all, in the brain, skeletal muscle and heart.

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[2]
Melanoma	DIS1RRCY	Limited	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Cell division cycle-associated protein 4 (CDCA4).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cell division cycle-associated protein 4 (CDCA4).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Cell division cycle-associated protein 4 (CDCA4).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Cell division cycle-associated protein 4 (CDCA4).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Cell division cycle-associated protein 4 (CDCA4).	[8]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cell division cycle-associated protein 4 (CDCA4).	[8]
Piroxicam	DMTK234	Approved	Piroxicam increases the expression of Cell division cycle-associated protein 4 (CDCA4).	[9]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cell division cycle-associated protein 4 (CDCA4).	[11]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Cell division cycle-associated protein 4 (CDCA4).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Cell division cycle-associated protein 4 (CDCA4).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cell division cycle-associated protein 4 (CDCA4).	[15]

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 increases the methylation of Cell division cycle-associated protein 4 (CDCA4).	[10]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Cell division cycle-associated protein 4 (CDCA4).	[13]

References

• [1] CDCA4, a downstream gene of the Nrf2 signaling pathway, regulates cell proliferation and apoptosis in the MCF?/ADM human breast cancer cell line.Mol Med Rep. 2018 Jan;17(1):1507-1512. doi: 10.3892/mmr.2017.8095. Epub 2017 Nov 15.
• [2] Knockdown of cell division cycle-associated protein 4 expression inhibits proliferation of triple negative breast cancer MDA-MB-231 cells in vitro and in vivo.Oncol Lett. 2019 May;17(5):4393-4400. doi: 10.3892/ol.2019.10077. Epub 2019 Feb 26.
• [3] MicroRNA-15a inhibits the growth and invasiveness of malignant melanoma and directly targets on CDCA4 gene.Tumour Biol. 2016 Oct;37(10):13941-13950. doi: 10.1007/s13277-016-5271-z. Epub 2016 Aug 4.
• [4] 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.
• [5] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [8] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [9] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [10] 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.
• [11] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [12] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [13] 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.
• [14] 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.
• [15] 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.