Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7ROIJF)

• DOT Name: DnaJ homolog subfamily C member 3 (DNAJC3)
• Synonyms: Endoplasmic reticulum DNA J domain-containing protein 6; ER-resident protein ERdj6; ERdj6; Interferon-induced, double-stranded RNA-activated protein kinase inhibitor; Protein kinase inhibitor of 58 kDa; Protein kinase inhibitor p58
• Gene Name: DNAJC3
• Related Disease:
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Hypothyroidism
  Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome
  Marinesco-Sjogren syndrome
  Osteosarcoma
  Prostate cancer
  Prostate neoplasm
  Type-1/2 diabetes
  Colorectal carcinoma
  Non-insulin dependent diabetes
  Polyposis
• UniProt ID: DNJC3_HUMAN
• PDB ID: 2Y4T; 2Y4U
• Pfam ID: PF00226 ; PF00515 ; PF13432 ; PF14559 ; PF13181
• Sequence:
  MVAPGSVTSRLGSVFPFLLVLVDLQYEGAECGVNADVEKHLELGKKLLAAGQLADALSQF
  HAAVDGDPDNYIAYYRRATVFLAMGKSKAALPDLTKVIQLKMDFTAARLQRGHLLLKQGK
  LDEAEDDFKKVLKSNPSENEEKEAQSQLIKSDEMQRLRSQALNAFGSGDYTAAIAFLDKI
  LEVCVWDAELRELRAECFIKEGEPRKAISDLKAASKLKNDNTEAFYKISTLYYQLGDHEL
  SLSEVRECLKLDQDHKRCFAHYKQVKKLNKLIESAEELIRDGRYTDATSKYESVMKTEPS
  IAEYTVRSKERICHCFSKDEKPVEAIRVCSEVLQMEPDNVNALKDRAEAYLIEEMYDEAI
  QDYETAQEHNENDQQIREGLEKAQRLLKQSQKRDYYKILGVKRNAKKQEIIKAYRKLALQ
  WHPDNFQNEEEKKKAEKKFIDIAAAKEVLSDPEMRKKFDDGEDPLDAESQQGGGGNPFHR
  SWNSWQGFNPFSSGGPFRFKFHFN
• Function: Involved in the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Acts as a negative regulator of the EIF2AK4/GCN2 kinase activity by preventing the phosphorylation of eIF-2-alpha at 'Ser-52' and hence attenuating general protein synthesis under ER stress, hypothermic and amino acid starving stress conditions. Co-chaperone of HSPA8/HSC70, it stimulates its ATPase activity. May inhibit both the autophosphorylation of EIF2AK2/PKR and the ability of EIF2AK2 to catalyze phosphorylation of the EIF2A. May inhibit EIF2AK3/PERK activity.
• Tissue Specificity: Widely expressed with high level in the pancreas and testis. Also expressed in cell lines with different levels.
• KEGG Pathway:
  Protein processing in endoplasmic reticulum (hsa04141)
  Influenza A (hsa05164)
• Reactome Pathway:
  XBP1(S) activates chaperone genes (R-HSA-381038)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)
  Neutrophil degranulation (R-HSA-6798695)
  Post-translational protein phosphorylation (R-HSA-8957275)
  PKR-mediated signaling (R-HSA-9833482)
  Viral mRNA Translation (R-HSA-192823)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[5]
Juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome	DIS2VPVR	Strong	Autosomal recessive	[6]
Marinesco-Sjogren syndrome	DISKEU0B	Strong	Biomarker	[7]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[8]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[8]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[9]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[10]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Autosomal dominant	[11]
Polyposis	DISZSPOK	Limited	Biomarker	[10]

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 DnaJ homolog subfamily C member 3 (DNAJC3).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DnaJ homolog subfamily C member 3 (DNAJC3).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[15]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[17]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[20]
Marinol	DM70IK5	Approved	Marinol increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[21]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[22]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[23]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[23]
Ursodeoxycholic acid	DMCUT21	Approved	Ursodeoxycholic acid decreases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[24]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[25]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[26]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[27]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[28]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[29]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[30]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[32]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[33]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[34]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[18]
L-Serine	DM6WPIS	Investigative	L-Serine increases the expression of DnaJ homolog subfamily C member 3 (DNAJC3).	[35]

References

• [1] Long noncoding RNA DNAJC3-AS1 promotes osteosarcoma progression via its sense-cognate gene DNAJC3.Cancer Med. 2019 Feb;8(2):761-772. doi: 10.1002/cam4.1955. Epub 2019 Jan 16.
• [2] ERp29 induces breast cancer cell growth arrest and survival through modulation of activation of p38 and upregulation of ER stress protein p58IPK.Lab Invest. 2012 Feb;92(2):200-13. doi: 10.1038/labinvest.2011.163. Epub 2011 Nov 7.
• [3] Characterization of a Threonine-Rich Cluster in Hepatitis C Virus Nonstructural Protein 5A and Its Contribution to Hyperphosphorylation.J Virol. 2018 Nov 27;92(24):e00737-18. doi: 10.1128/JVI.00737-18. Print 2018 Dec 15.
• [4] Protein kinase R is increased and is functional in hepatitis C virus-related hepatocellular carcinoma.Am J Gastroenterol. 2003 Nov;98(11):2528-34. doi: 10.1111/j.1572-0241.2003.08663.x.
• [5] Expanding the phenotype of DNAJC3 mutations: A case with hypothyroidism additionally to diabetes mellitus and multisystemic neurodegeneration.Clin Genet. 2017 Nov;92(5):561-562. doi: 10.1111/cge.13069. Epub 2017 Sep 21.
• [6] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [7] Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. Am J Hum Genet. 2014 Dec 4;95(6):689-97. doi: 10.1016/j.ajhg.2014.10.013. Epub 2014 Nov 20.
• [8] Identification of genes potentially involved in the acquisition of androgen-independent and metastatic tumor growth in an autochthonous genetically engineered mouse prostate cancer model.Prostate. 2007 Jan 1;67(1):83-106. doi: 10.1002/pros.20505.
• [9] DNAJC3 mutation in Thai familial type 2 diabetes mellitus.Int J Mol Med. 2018 Aug;42(2):1064-1073. doi: 10.3892/ijmm.2018.3678. Epub 2018 May 14.
• [10] Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer.Gut. 2004 Apr;53(4):573-80. doi: 10.1136/gut.2003.030841.
• [11] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [12] 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.
• [13] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [14] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [19] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [20] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [21] Delta9-tetrahydrocannabinol inhibits cytotrophoblast cell proliferation and modulates gene transcription. Mol Hum Reprod. 2006 May;12(5):321-33. doi: 10.1093/molehr/gal036. Epub 2006 Apr 5.
• [22] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [23] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [24] Ursodeoxycholic acid but not tauroursodeoxycholic acid inhibits proliferation and differentiation of human subcutaneous adipocytes. PLoS One. 2013 Dec 3;8(12):e82086. doi: 10.1371/journal.pone.0082086. eCollection 2013.
• [25] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [26] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [27] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [28] 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.
• [29] 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.
• [30] Protective effect against Parkinson's disease-related insults through the activation of XBP1. Brain Res. 2009 Feb 27;1257:16-24. doi: 10.1016/j.brainres.2008.11.104. Epub 2008 Dec 16.
• [31] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [32] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.
• [33] Overexpression of p58ipk protects neuroblastoma against paraquat-induced toxicity. Int J Clin Exp Pathol. 2017 Aug 1;10(8):8233-8242. eCollection 2017.
• [34] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [35] Mechanisms of L-Serine Neuroprotection in vitro Include ER Proteostasis Regulation. Neurotox Res. 2018 Jan;33(1):123-132. doi: 10.1007/s12640-017-9829-3. Epub 2017 Nov 2.