Details of Drug Off-Target (DOT)

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

• DOT Name: DnaJ homolog subfamily B member 6 (DNAJB6)
• Synonyms: HHDJ1; Heat shock protein J2; HSJ-2; MRJ; MSJ-1
• Gene Name: DNAJB6
• Related Disease:
  Inclusion body myositis
  Muscular dystrophy, limb-girdle, autosomal dominant
  Oculopharyngeal muscular dystrophy
  Adenocarcinoma
  Advanced cancer
  Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Carcinoma of esophagus
  Colorectal carcinoma
  Distal myopathy
  Esophageal cancer
  Fibrolamellar liver cancer
  Huntington disease
  Invasive ductal breast carcinoma
  Melanoma
  Myofibrillar myopathy
  Myopathy
  Neoplasm of esophagus
  Parkinson disease
  Muscular dystrophy
  Parkinsonian disorder
  Gastric cancer
  GNE myopathy
  Limb-girdle muscular dystrophy
  Rheumatoid arthritis
  X-linked myopathy with excessive autophagy
• UniProt ID: DNJB6_HUMAN
• PDB ID: 6U3R; 6U3S; 7JSQ; 7QBY
• Pfam ID: PF00226
• Sequence:
  MVDYYEVLGVQRHASPEDIKKAYRKLALKWHPDKNPENKEEAERKFKQVAEAYEVLSDAK
  KRDIYDKYGKEGLNGGGGGGSHFDSPFEFGFTFRNPDDVFREFFGGRDPFSFDFFEDPFE
  DFFGNRRGPRGSRSRGTGSFFSAFSGFPSFGSGFSSFDTGFTSFGSLGHGGLTSFSSTSF
  GGSGMGNFKSISTSTKMVNGRKITTKRIVENGQERVEVEEDGQLKSLTINGVADDDALAE
  ERMRRGQNALPAQPAGLRPPKPPRPASLLRHAPHCLSEEEGEQDRPRAPGPWDPLASAAG
  LKEGGKRKKQKQREESKKKKSTKGNH
• Function: Has a stimulatory effect on the ATPase activity of HSP70 in a dose-dependent and time-dependent manner and hence acts as a co-chaperone of HSP70. Plays an indispensable role in the organization of KRT8/KRT18 filaments. Acts as an endogenous molecular chaperone for neuronal proteins including huntingtin. Suppresses aggregation and toxicity of polyglutamine-containing, aggregation-prone proteins. Also reduces cellular toxicity and caspase-3 activity ; [Isoform B]: Isoform B but not isoform A inhibits huntingtin aggregation.
• Tissue Specificity: Widely expressed. Highest levels in testis and brain, and lower levels in heart, spleen, intestine, ovary, placenta, lung, kidney, pancreas, thymus, prostate, skeletal muscle, liver and leukocytes. In testis, expressed in germ cells in the earlier stages of differentiation pathway as well as in spermatids. In brain, expressed at a higher level in hippocampus and thalamus and a lower level in amygdala, substantia nigra, corpus callosum and caudate nucleus.
• Reactome Pathway: Regulation of HSF1-mediated heat shock response (R-HSA-3371453)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Inclusion body myositis	DISZXXG5	Definitive	Biomarker	[1]
Muscular dystrophy, limb-girdle, autosomal dominant	DISMMHPT	Definitive	Autosomal dominant	[2]
Oculopharyngeal muscular dystrophy	DISF4G07	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)	DISSYZJ0	Strong	Autosomal dominant	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Distal myopathy	DIS7F5R0	Strong	Genetic Variation	[8]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[7]
Fibrolamellar liver cancer	DISUDA2P	Strong	Altered Expression	[9]
Huntington disease	DISQPLA4	Strong	Altered Expression	[10]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[6]
Melanoma	DIS1RRCY	Strong	Biomarker	[6]
Myofibrillar myopathy	DISF24LW	Strong	Biomarker	[11]
Myopathy	DISOWG27	Strong	Genetic Variation	[8]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[7]
Parkinson disease	DISQVHKL	Strong	Biomarker	[12]
Muscular dystrophy	DISJD6P7	Disputed	Genetic Variation	[13]
Parkinsonian disorder	DISHGY45	Disputed	Genetic Variation	[14]
Gastric cancer	DISXGOUK	Limited	Biomarker	[15]
GNE myopathy	DIS73X4W	Limited	Biomarker	[16]
Limb-girdle muscular dystrophy	DISI9Y1Z	Limited	Genetic Variation	[13]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[17]
X-linked myopathy with excessive autophagy	DIS1AFQH	Limited	Genetic Variation	[18]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[19]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[20]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[22]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[23]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[24]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[25]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[26]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[27]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[27]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[28]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[29]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[30]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[30]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[31]
Isoflavone	DM7U58J	Phase 4	Isoflavone affects the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[32]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[33]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[34]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[35]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[39]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of DnaJ homolog subfamily B member 6 (DNAJB6).	[40]

4 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 DnaJ homolog subfamily B member 6 (DNAJB6).	[36]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of DnaJ homolog subfamily B member 6 (DNAJB6).	[37]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of DnaJ homolog subfamily B member 6 (DNAJB6).	[38]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of DnaJ homolog subfamily B member 6 (DNAJB6).	[38]

References

• [1] Non-pathogenic protein aggregates in skeletal muscle in MLF1 transgenic mice.J Neurol Sci. 2008 Jan 15;264(1-2):77-86. doi: 10.1016/j.jns.2007.07.027. Epub 2007 Sep 12.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Overexpression of DNAJB6 promotes colorectal cancer cell invasion through an IQGAP1/ERK-dependent signaling pathway.Mol Carcinog. 2015 Oct;54(10):1205-13. doi: 10.1002/mc.22194. Epub 2014 Jul 7.
• [4] Emerging roles and underlying molecular mechanisms of DNAJB6 in cancer.Oncotarget. 2016 Aug 16;7(33):53984-53996. doi: 10.18632/oncotarget.9803.
• [5] Mutations affecting the cytoplasmic functions of the co-chaperone DNAJB6 cause limb-girdle muscular dystrophy. Nat Genet. 2012 Feb 26;44(4):450-5, S1-2. doi: 10.1038/ng.1103.
• [6] Large isoform of MRJ (DNAJB6) reduces malignant activity of breast cancer.Breast Cancer Res. 2008;10(2):R22. doi: 10.1186/bcr1874. Epub 2008 Mar 7.
• [7] Nuclear Localization of DNAJB6 Is Associated With Survival of Patients With Esophageal Cancer and Reduces AKT Signaling and Proliferation of Cancer Cells.Gastroenterology. 2015 Dec;149(7):1825-1836.e5. doi: 10.1053/j.gastro.2015.08.025. Epub 2015 Aug 22.
• [8] Novel mutations in DNAJB6 cause LGMD1D and distal myopathy in French families.Eur J Neurol. 2018 May;25(5):790-794. doi: 10.1111/ene.13598. Epub 2018 Mar 30.
• [9] An acquired scaffolding function of the DNAJ-PKAc fusion contributes to oncogenic signaling in fibrolamellar carcinoma.Elife. 2019 May 7;8:e44187. doi: 10.7554/eLife.44187.
• [10] Astrocytic expression of the chaperone DNAJB6 results in non-cell autonomous protection in Huntington's disease.Neurobiol Dis. 2019 Apr;124:108-117. doi: 10.1016/j.nbd.2018.10.017. Epub 2018 Nov 5.
• [11] Diagnostically important muscle pathology in DNAJB6 mutated LGMD1D.Acta Neuropathol Commun. 2016 Feb 5;4:9. doi: 10.1186/s40478-016-0276-9.
• [12] The Short Isoform of DNAJB6 Protects against 1-Methyl-4-phenylpridinium Ion-Induced Apoptosis in LN18 Cells via Inhibiting Both ROS Formation and Mitochondrial Membrane Potential Loss.Oxid Med Cell Longev. 2017;2017:7982389. doi: 10.1155/2017/7982389. Epub 2017 Feb 9.
• [13] Intrafamilial variability of limb-girdle muscular dystrophy, LGMD1D type.Eur J Med Genet. 2020 Feb;63(2):103655. doi: 10.1016/j.ejmg.2019.04.012. Epub 2019 Apr 27.
• [14] DNAJC13 p.Asn855Ser, implicated in familial parkinsonism, alters membrane dynamics of sorting nexin 1.Neurosci Lett. 2019 Jul 27;706:114-122. doi: 10.1016/j.neulet.2019.04.043. Epub 2019 May 11.
• [15] HLJ1 (DNAJB4) Gene Is a Novel Biomarker Candidate in Breast Cancer.OMICS. 2017 May;21(5):257-265. doi: 10.1089/omi.2017.0016.
• [16] Genetic interaction of hnRNPA2B1 and DNAJB6 in a Drosophila model of multisystem proteinopathy.Hum Mol Genet. 2016 Mar 1;25(5):936-50. doi: 10.1093/hmg/ddv627. Epub 2016 Jan 6.
• [17] Isolation of an IgG monoclonal anti-dnaJ antibody from an immunoglobulin combinatorial library from a patient with rheumatoid arthritis.J Rheumatol. 1999 Jul;26(7):1439-45.
• [18] DNAJB6 myopathy: a vacuolar myopathy with childhood onset.Muscle Nerve. 2014 Apr;49(4):607-10. doi: 10.1002/mus.24106. Epub 2014 Feb 24.
• [19] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [20] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [21] 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.
• [22] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Darinaparsin induces a unique cellular response and is active in an arsenic trioxide-resistant myeloma cell line. Mol Cancer Ther. 2009 May;8(5):1197-206.
• [27] 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.
• [28] Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma. PLoS One. 2011;6(8):e23569.
• [29] Chronic cyclophosphamide exposure alters the profile of rat sperm nuclear matrix proteins. Biol Reprod. 2007 Aug;77(2):303-11. doi: 10.1095/biolreprod.107.060244. Epub 2007 May 2.
• [30] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [31] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [32] Soy isoflavones alter expression of genes associated with cancer progression, including interleukin-8, in androgen-independent PC-3 human prostate cancer cells. J Nutr. 2006 Jan;136(1):75-82.
• [33] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [34] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [35] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [36] 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.
• [37] 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.
• [38] 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.
• [39] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.
• [40] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.