Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD2EG0R)

• DOT Name: DnaJ homolog subfamily C member 10 (DNAJC10)
• Synonyms: EC 1.8.4.-; Endoplasmic reticulum DNA J domain-containing protein 5; ER-resident protein ERdj5; ERdj5; Macrothioredoxin; MTHr
• Gene Name: DNAJC10
• Related Disease:
  Advanced cancer
  Benign neoplasm
  Breast cancer
  Breast carcinoma
  Hepatocellular carcinoma
  Neoplasm
  Prostate cancer
  Prostate neoplasm
  Autoimmune disease
  Neuroblastoma
  Sjogren syndrome
  Parkinsonian disorder
• UniProt ID: DJC10_HUMAN
• EC Number: 1.8.4.-
• Pfam ID: PF00226 ; PF00085
• Sequence:
  MGVWLNKDDYIRDLKRIILCFLIVYMAILVGTDQDFYSLLGVSKTASSREIRQAFKKLAL
  KLHPDKNPNNPNAHGDFLKINRAYEVLKDEDLRKKYDKYGEKGLEDNQGGQYESWNYYRY
  DFGIYDDDPEIITLERREFDAAVNSGELWFVNFYSPGCSHCHDLAPTWRDFAKEVDGLLR
  IGAVNCGDDRMLCRMKGVNSYPSLFIFRSGMAPVKYHGDRSKESLVSFAMQHVRSTVTEL
  WTGNFVNSIQTAFAAGIGWLITFCSKGGDCLTSQTRLRLSGMLDGLVNVGWMDCATQDNL
  CKSLDITTSTTAYFPPGATLNNKEKNSILFLNSLDAKEIYLEVIHNLPDFELLSANTLED
  RLAHHRWLLFFHFGKNENSNDPELKKLKTLLKNDHIQVGRFDCSSAPDICSNLYVFQPSL
  AVFKGQGTKEYEIHHGKKILYDILAFAKESVNSHVTTLGPQNFPANDKEPWLVDFFAPWC
  PPCRALLPELRRASNLLYGQLKFGTLDCTVHEGLCNMYNIQAYPTTVVFNQSNIHEYEGH
  HSAEQILEFIEDLMNPSVVSLTPTTFNELVTQRKHNEVWMVDFYSPWCHPCQVLMPEWKR
  MARTLTGLINVGSIDCQQYHSFCAQENVQRYPEIRFFPPKSNKAYHYHSYNGWNRDAYSL
  RIWGLGFLPQVSTDLTPQTFSEKVLQGKNHWVIDFYAPWCGPCQNFAPEFELLARMIKGK
  VKAGKVDCQAYAQTCQKAGIRAYPTVKFYFYERAKRNFQEEQINTRDAKAIAALISEKLE
  TLRNQGKRNKDEL
• Function: Endoplasmic reticulum disulfide reductase involved both in the correct folding of proteins and degradation of misfolded proteins. Required for efficient folding of proteins in the endoplasmic reticulum by catalyzing the removal of non-native disulfide bonds formed during the folding of proteins, such as LDLR. Also involved in endoplasmic reticulum-associated degradation (ERAD) by reducing incorrect disulfide bonds in misfolded glycoproteins recognized by EDEM1. Interaction with HSPA5 is required its activity, not for the disulfide reductase activity, but to facilitate the release of DNAJC10 from its substrate. Promotes apoptotic signaling pathway in response to endoplasmic reticulum stress.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Therapeutic	[1]
Benign neoplasm	DISDUXAD	Strong	Therapeutic	[1]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Therapeutic	[1]
Prostate cancer	DISF190Y	Strong	Biomarker	[4]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	moderate	Biomarker	[5]
Neuroblastoma	DISVZBI4	moderate	Biomarker	[6]
Sjogren syndrome	DISUBX7H	moderate	Biomarker	[5]
Parkinsonian disorder	DISHGY45	Disputed	Genetic Variation	[7]

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 10 (DNAJC10).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of DnaJ homolog subfamily C member 10 (DNAJC10).	[19]

15 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 10 (DNAJC10).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[12]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[13]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[13]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[14]
Nefazodone	DM4ZS8M	Approved	Nefazodone increases the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[15]
Atazanavir	DMSYRBX	Approved	Atazanavir increases the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[15]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[16]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[18]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[1]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[20]
Okadaic acid	DM47CO1	Investigative	Okadaic acid increases the expression of DnaJ homolog subfamily C member 10 (DNAJC10).	[21]

References

• [1] Targeting homeostatic mechanisms of endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57. Br J Cancer. 2007 Apr 10;96(7):1062-71. doi: 10.1038/sj.bjc.6603672. Epub 2007 Mar 13.
• [2] Significant association between ERCC2 and MTHR polymorphisms and breast cancer susceptibility in Moroccan population: genotype and haplotype analysis in a case-control study.BMC Cancer. 2018 Mar 15;18(1):292. doi: 10.1186/s12885-018-4214-z.
• [3] Increased expression of specific thioredoxin family proteins; a pilot immunohistochemical study on human hepatocellular carcinoma.Int J Immunopathol Pharmacol. 2007 Jan-Mar;20(1):17-24. doi: 10.1177/039463200702000103.
• [4] 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.
• [5] Ablation of the Chaperone Protein ERdj5 Results in a Sjgren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients.Front Immunol. 2019 Mar 22;10:506. doi: 10.3389/fimmu.2019.00506. eCollection 2019.
• [6] ERdj5 sensitizes neuroblastoma cells to endoplasmic reticulum stress-induced apoptosis.J Biol Chem. 2009 Mar 6;284(10):6282-90. doi: 10.1074/jbc.M806189200. Epub 2009 Jan 4.
• [7] DNAJC proteins and pathways to parkinsonism.FEBS J. 2019 Aug;286(16):3080-3094. doi: 10.1111/febs.14936. Epub 2019 Jun 20.
• [8] 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.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] 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.
• [12] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [13] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [14] Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
• [15] Robustness testing and optimization of an adverse outcome pathway on cholestatic liver injury. Arch Toxicol. 2020 Apr;94(4):1151-1172. doi: 10.1007/s00204-020-02691-9. Epub 2020 Mar 10.
• [16] 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.
• [17] Targeting homeostatic mechanisms of endoplasmic reticulum stress to increase susceptibility of cancer cells to fenretinide-induced apoptosis: the role of stress proteins ERdj5 and ERp57. Br J Cancer. 2007 Apr 10;96(7):1062-71. doi: 10.1038/sj.bjc.6603672. Epub 2007 Mar 13.
• [18] Comparison of quantitation methods in proteomics to define relevant toxicological information on AhR activation of HepG2 cells by BaP. Toxicology. 2021 Jan 30;448:152652. doi: 10.1016/j.tox.2020.152652. Epub 2020 Dec 2.
• [19] 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.
• [20] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [21] Whole genome mRNA transcriptomics analysis reveals different modes of action of the diarrheic shellfish poisons okadaic acid and dinophysis toxin-1 versus azaspiracid-1 in Caco-2 cells. Toxicol In Vitro. 2018 Feb;46:102-112.