Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTTBV70J)

DOT Name	Cullin-4A (CUL4A)
Synonyms	CUL-4A
Gene Name	CUL4A
Related Disease	Type-1 diabetes ( ) Alzheimer disease ( ) Alzheimer disease 3 ( ) Anemia ( ) Atrial fibrillation ( ) Bone osteosarcoma ( ) Breast cancer ( ) Breast carcinoma ( ) Carcinoma of esophagus ( ) Colon cancer ( ) Colon carcinoma ( ) Epithelial ovarian cancer ( ) Esophageal cancer ( ) Esophageal squamous cell carcinoma ( ) Hepatocellular carcinoma ( ) Intrahepatic cholangiocarcinoma ( ) Liver cancer ( ) Lung cancer ( ) Lung carcinoma ( ) Malignant pleural mesothelioma ( ) Malignant soft tissue neoplasm ( ) Mesothelioma ( ) Neoplasm ( ) Neoplasm of esophagus ( ) Osteosarcoma ( ) Ovarian cancer ( ) Ovarian neoplasm ( ) Pheochromocytoma ( ) Plasma cell myeloma ( ) Sarcoma ( ) Skin cancer ( ) Stevens-Johnson syndrome ( ) Toxic epidermal necrolysis ( ) Carcinoma ( ) Familial atrial fibrillation ( ) Metastatic malignant neoplasm ( ) Non-small-cell lung cancer ( ) Prostate cancer ( ) Prostate carcinoma ( ) Bipolar disorder ( ) Carcinoma of liver and intrahepatic biliary tract ( ) Chronic obstructive pulmonary disease ( ) Colorectal carcinoma ( ) Gastric cancer ( ) Lung neoplasm ( ) Stomach cancer ( )
UniProt ID	CUL4A_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
PDB ID	2HYE; 4A0K; 7OKQ; 7OPC; 7OPD; 8B3I
Pfam ID	PF00888 ; PF10557
Sequence	MADEAPRKGSFSALVGRTNGLTKPAALAAAPAKPGGAGGSKKLVIKNFRDRPRLPDNYTQ DTWRKLHEAVRAVQSSTSIRYNLEELYQAVENLCSHKVSPMLYKQLRQACEDHVQAQILP FREDSLDSVLFLKKINTCWQDHCRQMIMIRSIFLFLDRTYVLQNSTLPSIWDMGLELFRT HIISDKMVQSKTIDGILLLIERERSGEAVDRSLLRSLLGMLSDLQVYKDSFELKFLEETN CLYAAEGQRLMQEREVPEYLNHVSKRLEEEGDRVITYLDHSTQKPLIACVEKQLLGEHLT AILQKGLDHLLDENRVPDLAQMYQLFSRVRGGQQALLQHWSEYIKTFGTAIVINPEKDKD MVQDLLDFKDKVDHVIEVCFQKNERFVNLMKESFETFINKRPNKPAELIAKHVDSKLRAG NKEATDEELERTLDKIMILFRFIHGKDVFEAFYKKDLAKRLLVGKSASVDAEKSMLSKLK HECGAAFTSKLEGMFKDMELSKDIMVHFKQHMQNQSDSGPIDLTVNILTMGYWPTYTPME VHLTPEMIKLQEVFKAFYLGKHSGRKLQWQTTLGHAVLKAEFKEGKKEFQVSLFQTLVLL MFNEGDGFSFEEIKMATGIEDSELRRTLQSLACGKARVLIKSPKGKEVEDGDKFIFNGEF KHKLFRIKINQIQMKETVEEQVSTTERVFQDRQYQIDAAIVRIMKMRKTLGHNLLVSELY NQLKFPVKPGDLKKRIESLIDRDYMERDKDNPNQYHYVA
Function	Core component of multiple cullin-RING-based E3 ubiquitin-protein ligase complexes which mediate the ubiquitination of target proteins. As a scaffold protein may contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and is inhibited by the association of the deneddylated cullin subunit with TIP120A/CAND1. The functional specificity of the E3 ubiquitin-protein ligase complex depends on the variable substrate recognition component. DCX(DET1-COP1) directs ubiquitination of JUN. DCX(DDB2) directs ubiquitination of XPC. DCX(DDB2) ubiquitinates histones H3-H4 and is required for efficient histone deposition during replication-coupled (H3.1) and replication-independent (H3.3) nucleosome assembly, probably by facilitating the transfer of H3 from ASF1A/ASF1B to other chaperones involved in histone deposition. DCX(DTL) plays a role in PCNA-dependent polyubiquitination of CDT1 and MDM2-dependent ubiquitination of p53/TP53 in response to radiation-induced DNA damage and during DNA replication. DCX(DTL) directs autoubiquitination of DTL. In association with DDB1 and SKP2 probably is involved in ubiquitination of CDKN1B/p27kip. Is involved in ubiquitination of HOXA9. The DDB1-CUL4A-DTL E3 ligase complex regulates the circadian clock function by mediating the ubiquitination and degradation of CRY1. A number of DCX complexes (containing either TRPC4AP or DCAF12 as substrate-recognition component) are part of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The DCX(AMBRA1) complex is a master regulator of the transition from G1 to S cell phase by mediating ubiquitination of phosphorylated cyclin-D (CCND1, CCND2 and CCND3). The DCX(AMBRA1) complex also acts as a regulator of Cul5-RING (CRL5) E3 ubiquitin-protein ligase complexes by mediating ubiquitination and degradation of Elongin-C (ELOC) component of CRL5 complexes. With CUL4B, contributes to ribosome biogenesis.
KEGG Pathway	Nucleotide excision repair (hsa03420 ) Ubiquitin mediated proteolysis (hsa04120 ) Human immunodeficiency virus 1 infection (hsa05170 )
Reactome Pathway	DNA Damage Recognition in GG-NER (R-HSA-5696394 ) Formation of Incision Complex in GG-NER (R-HSA-5696395 ) Dual Incision in GG-NER (R-HSA-5696400 ) Formation of TC-NER Pre-Incision Complex (R-HSA-6781823 ) Transcription-Coupled Nucleotide Excision Repair (TC-NER) (R-HSA-6781827 ) Dual incision in TC-NER (R-HSA-6782135 ) Gap-filling DNA repair synthesis and ligation in TC-NER (R-HSA-6782210 ) Neddylation (R-HSA-8951664 ) Recognition of DNA damage by PCNA-containing replication complex (R-HSA-110314 )

Molecular Interaction Atlas (MIA) of This DOT

46 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Alzheimer disease 3	DISVT69G	Strong	Biomarker	[2]
Anemia	DISTVL0C	Strong	Biomarker	[3]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[7]
Colon cancer	DISVC52G	Strong	Altered Expression	[8]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[8]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[7]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[10]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Altered Expression	[11]
Liver cancer	DISDE4BI	Strong	Biomarker	[12]
Lung cancer	DISCM4YA	Strong	Biomarker	[13]
Lung carcinoma	DISTR26C	Strong	Biomarker	[13]
Malignant pleural mesothelioma	DIST2R60	Strong	Altered Expression	[14]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Altered Expression	[15]
Mesothelioma	DISKWK9M	Strong	Altered Expression	[14]
Neoplasm	DISZKGEW	Strong	Biomarker	[8]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[7]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Pheochromocytoma	DIS56IFV	Strong	Biomarker	[16]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[17]
Sarcoma	DISZDG3U	Strong	Altered Expression	[15]
Skin cancer	DISTM18U	Strong	Biomarker	[18]
Stevens-Johnson syndrome	DISZG4YX	Strong	Biomarker	[19]
Toxic epidermal necrolysis	DISIWPFR	Strong	Biomarker	[19]
Carcinoma	DISH9F1N	moderate	Altered Expression	[20]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[4]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[21]
Non-small-cell lung cancer	DIS5Y6R9	moderate	Altered Expression	[22]
Prostate cancer	DISF190Y	moderate	Biomarker	[23]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[23]
Bipolar disorder	DISAM7J2	Limited	Genetic Variation	[24]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Biomarker	[12]
Chronic obstructive pulmonary disease	DISQCIRF	Limited	Biomarker	[25]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[26]
Gastric cancer	DISXGOUK	Limited	Biomarker	[27]
Lung neoplasm	DISVARNB	Limited	Biomarker	[13]
Stomach cancer	DISKIJSX	Limited	Biomarker	[27]
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⏷ Show the Full List of 46 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

Jump to Detail Molecular Interaction Atlas of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	Cullin-4A (CUL4A) affects the response to substance of Topotecan.	[45]
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3 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 Cullin-4A (CUL4A).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cullin-4A (CUL4A).	[41]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Cullin-4A (CUL4A).	[43]
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13 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 Cullin-4A (CUL4A).	[29]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cullin-4A (CUL4A).	[30]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cullin-4A (CUL4A).	[31]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cullin-4A (CUL4A).	[32]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Cullin-4A (CUL4A).	[33]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cullin-4A (CUL4A).	[34]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Cullin-4A (CUL4A).	[35]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Cullin-4A (CUL4A).	[36]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Cullin-4A (CUL4A).	[37]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Cullin-4A (CUL4A).	[38]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Cullin-4A (CUL4A).	[39]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Cullin-4A (CUL4A).	[42]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Cullin-4A (CUL4A).	[44]
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⏷ Show the Full List of 13 Drug(s)

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Cullin-4A (CUL4A).	[40]
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References

1	Inflammation-dependent downregulation of miR-194-5p contributes to human intervertebral disc degeneration by targeting CUL4A and CUL4B.J Cell Physiol. 2019 Nov;234(11):19977-19989. doi: 10.1002/jcp.28595. Epub 2019 Apr 3.
2	A MicroRNA Derived from Adenovirus Virus-Associated RNAII Promotes Virus Infection via Posttranscriptional Gene Silencing.J Virol. 2019 Jan 4;93(2):e01265-18. doi: 10.1128/JVI.01265-18. Print 2019 Jan 15.
3	Cul4a promotes zebrafish primitive erythropoiesis via upregulating scl and gata1 expression.Cell Death Dis. 2019 May 17;10(6):388. doi: 10.1038/s41419-019-1629-7.
4	Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
5	CUL4A expression in pediatric osteosarcoma tissues and its effect on cell growth in osteosarcoma cells.Tumour Biol. 2016 Jun;37(6):8139-44. doi: 10.1007/s13277-015-4715-1. Epub 2015 Dec 29.
6	Association of mRNA expression levels of Cullin family members with prognosis in breast cancer: An online database analysis.Medicine (Baltimore). 2019 Aug;98(31):e16625. doi: 10.1097/MD.0000000000016625.
7	Overexpression of Cullin4A correlates with a poor prognosis and tumor progression in esophageal squamous cell carcinoma.Int J Clin Oncol. 2020 Mar;25(3):446-455. doi: 10.1007/s10147-019-01547-2. Epub 2019 Sep 18.
8	High Expressions of CUL4A and TP53 in Colorectal Cancer Predict Poor Survival.Cell Physiol Biochem. 2018;51(6):2829-2842. doi: 10.1159/000496013. Epub 2018 Dec 18.
9	miR?77 targets CUL4A and regulates metastatic capability in ovarian cancer.Int J Mol Med. 2018 Jun;41(6):3147-3156. doi: 10.3892/ijmm.2018.3540. Epub 2018 Mar 7.
10	CUL4A facilitates hepatocarcinogenesis by promoting cell cycle progression and epithelial-mesenchymal transition.Sci Rep. 2015 Nov 23;5:17006. doi: 10.1038/srep17006.
11	CUL4A overexpression as an independent adverse prognosticator in intrahepatic cholangiocarcinoma.BMC Cancer. 2017 Jun 2;17(1):395. doi: 10.1186/s12885-017-3389-z.
12	Investigation of the role of cullin 4A overexpression in human liver cancer.Mol Med Rep. 2018 Sep;18(3):2531-2540. doi: 10.3892/mmr.2018.9233. Epub 2018 Jun 29.
13	Cul4A Modulates Invasion and Metastasis of Lung Cancer Through Regulation of ANXA10.Cancers (Basel). 2019 May 2;11(5):618. doi: 10.3390/cancers11050618.
14	Cul4A overexpression associated with Gli1 expression in malignant pleural mesothelioma.J Cell Mol Med. 2015 Oct;19(10):2385-96. doi: 10.1111/jcmm.12620. Epub 2015 Jul 27.
15	Analysis of DNA repair-related genes in breast cancer reveals CUL4A ubiquitin ligase as a novel biomarker of trabectedin response.Mol Cancer Ther. 2013 Apr;12(4):530-41. doi: 10.1158/1535-7163.MCT-12-0768. Epub 2013 Jan 30.
16	Overexpression of the human ubiquitin E3 ligase CUL4A alleviates hypoxia-reoxygenation injury in pheochromocytoma (PC12) cells.Biochem Biophys Res Commun. 2011 Dec 16;416(3-4):403-8. doi: 10.1016/j.bbrc.2011.11.054. Epub 2011 Nov 19.
17	CUL4A as a marker and potential therapeutic target in multiple myeloma.Tumour Biol. 2017 Jul;39(7):1010428317703923. doi: 10.1177/1010428317703923.
18	The CUL4A ubiquitin ligase is a potential therapeutic target in skin cancer and other malignancies.Chin J Cancer. 2013 Sep;32(9):478-82. doi: 10.5732/cjc.012.10279. Epub 2013 Jul 12.
19	Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
20	Dysregulation of CUL4A and CUL4B Ubiquitin Ligases in Lung Cancer.J Biol Chem. 2017 Feb 17;292(7):2966-2978. doi: 10.1074/jbc.M116.765230. Epub 2016 Dec 14.
21	Knockdown of CUL4A inhibits invasion and induces apoptosis in osteosarcoma cells.Int J Immunopathol Pharmacol. 2015 Jun;28(2):263-9. doi: 10.1177/0394632015586656. Epub 2015 Jun 8.
22	Reduced miR-363-3p expression in non-small cell lung cancer is associated with gemcitabine resistance via targeting of CUL4A.Eur Rev Med Pharmacol Sci. 2019 Jan;23(2):649-659. doi: 10.26355/eurrev_201901_16879.
23	NRIP/DCAF6 stabilizes the androgen receptor protein by displacing DDB2 from the CUL4A-DDB1 E3 ligase complex in prostate cancer.Oncotarget. 2017 Mar 28;8(13):21501-21515. doi: 10.18632/oncotarget.15308.
24	Genome-wide association study identifies 30 loci associated with bipolar disorder.Nat Genet. 2019 May;51(5):793-803. doi: 10.1038/s41588-019-0397-8. Epub 2019 May 1.
25	The cullin4A is up-regulated in chronic obstructive pulmonary disease patient and contributes to epithelial-mesenchymal transition in small airway epithelium.Respir Res. 2019 May 6;20(1):84. doi: 10.1186/s12931-019-1048-4.
26	A Novel lncRNA, LINC00460, Affects Cell Proliferation and Apoptosis by Regulating KLF2 and CUL4A Expression in Colorectal Cancer.Mol Ther Nucleic Acids. 2018 Sep 7;12:684-697. doi: 10.1016/j.omtn.2018.06.012. Epub 2018 Jul 6.
27	KDM5D inhibit epithelial-mesenchymal transition of gastric cancer through demethylation in the promoter of Cul4A in male.J Cell Biochem. 2019 Aug;120(8):12247-12258. doi: 10.1002/jcb.27308. Epub 2019 Mar 12.
28	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.
29	Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
30	Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
31	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.
32	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.
33	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.
34	Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
35	Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
36	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.
37	Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
38	Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
39	Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
40	Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
41	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.
42	Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
43	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.
44	Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
45	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.