Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9R9G0H)

• DOT Name: Chromodomain-helicase-DNA-binding protein 1 (CHD1)
• Synonyms: CHD-1; EC 3.6.4.12; ATP-dependent helicase CHD1
• Gene Name: CHD1
• Related Disease:
  Nephrolithiasis, calcium oxalate
  Xeroderma pigmentosum group C
  Acute myelogenous leukaemia
  Adult lymphoma
  Advanced cancer
  Alzheimer disease
  Alzheimer disease 3
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal adenoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Gastric cancer
  Glioma
  leukaemia
  Leukemia
  Lymphoma
  Neoplasm
  Pediatric lymphoma
  Prostate carcinoma
  Prostate neoplasm
  Stomach cancer
  Carcinoma
  Pilarowski-Bjornsson syndrome
  Breast cancer
  Breast carcinoma
  Castration-resistant prostate carcinoma
  Metastatic malignant neoplasm
  Prostate cancer
• UniProt ID: CHD1_HUMAN
• PDB ID: 2B2T; 2B2U; 2B2V; 2B2W; 2B2Y; 2N39; 4B4C; 4NW2; 4O42; 5AFW
• EC Number: 3.6.4.12
• Pfam ID: PF18375 ; PF13907 ; PF00385 ; PF00271 ; PF00176
• Sequence:
  MNGHSDEESVRNSSGESSQSDDDSGSASGSGSGSSSGSSSDGSSSQSGSSDSDSGSESGS
  QSESESDTSRENKVQAKPPKVDGAEFWKSSPSILAVQRSAILKKQQQQQQQQQHQASSNS
  GSEEDSSSSEDSDDSSSEVKRKKHKDEDWQMSGSGSPSQSGSDSESEEEREKSSCDETES
  DYEPKNKVKSRKPQNRSKSKNGKKILGQKKRQIDSSEEDDDEEDYDNDKRSSRRQATVNV
  SYKEDEEMKTDSDDLLEVCGEDVPQPEEEEFETIERFMDCRIGRKGATGATTTIYAVEAD
  GDPNAGFEKNKEPGEIQYLIKWKGWSHIHNTWETEETLKQQNVRGMKKLDNYKKKDQETK
  RWLKNASPEDVEYYNCQQELTDDLHKQYQIVERIIAHSNQKSAAGYPDYYCKWQGLPYSE
  CSWEDGALISKKFQACIDEYFSRNQSKTTPFKDCKVLKQRPRFVALKKQPSYIGGHEGLE
  LRDYQLNGLNWLAHSWCKGNSCILADEMGLGKTIQTISFLNYLFHEHQLYGPFLLVVPLS
  TLTSWQREIQTWASQMNAVVYLGDINSRNMIRTHEWTHHQTKRLKFNILLTTYEILLKDK
  AFLGGLNWAFIGVDEAHRLKNDDSLLYKTLIDFKSNHRLLITGTPLQNSLKELWSLLHFI
  MPEKFSSWEDFEEEHGKGREYGYASLHKELEPFLLRRVKKDVEKSLPAKVEQILRMEMSA
  LQKQYYKWILTRNYKALSKGSKGSTSGFLNIMMELKKCCNHCYLIKPPDNNEFYNKQEAL
  QHLIRSSGKLILLDKLLIRLRERGNRVLIFSQMVRMLDILAEYLKYRQFPFQRLDGSIKG
  ELRKQALDHFNAEGSEDFCFLLSTRAGGLGINLASADTVVIFDSDWNPQNDLQAQARAHR
  IGQKKQVNIYRLVTKGSVEEDILERAKKKMVLDHLVIQRMDTTGKTVLHTGSAPSSSTPF
  NKEELSAILKFGAEELFKEPEGEEQEPQEMDIDEILKRAETHENEPGPLTVGDELLSQFK
  VANFSNMDEDDIELEPERNSKNWEEIIPEDQRRRLEEEERQKELEEIYMLPRMRNCAKQI
  SFNGSEGRRSRSRRYSGSDSDSISEGKRPKKRGRPRTIPRENIKGFSDAEIRRFIKSYKK
  FGGPLERLDAIARDAELVDKSETDLRRLGELVHNGCIKALKDSSSGTERTGGRLGKVKGP
  TFRISGVQVNAKLVISHEEELIPLHKSIPSDPEERKQYTIPCHTKAAHFDIDWGKEDDSN
  LLIGIYEYGYGSWEMIKMDPDLSLTHKILPDDPDKKPQAKQLQTRADYLIKLLSRDLAKK
  EALSGAGSSKRRKARAKKNKAMKSIKVKEEIKSDSSPLPSEKSDEDDDKLSESKSDGRER
  SKKSSVSDAPVHITASGEPVPISEESEELDQKTFSICKERMRPVKAALKQLDRPEKGLSE
  REQLEHTRQCLIKIGDHITECLKEYTNPEQIKQWRKNLWIFVSKFTEFDARKLHKLYKHA
  IKKRQESQQNSDQNSNLNPHVIRNPDVERLKENTNHDDSSRDSYSSDRHLTQYHDHHKDR
  HQGDSYKKSDSRKRPYSSFSNGKDHRDWDHYKQDSRYYSDREKHRKLDDHRSRDHRSNLE
  GSLKDRSHSDHRSHSDHRLHSDHRSSSEYTHHKSSRDYRYHSDWQMDHRASSSGPRSPLD
  QRSPYGSRSPFEHSVEHKSTPEHTWSSRKT
• Function: ATP-dependent chromatin-remodeling factor which functions as substrate recognition component of the transcription regulatory histone acetylation (HAT) complex SAGA. Regulates polymerase II transcription. Also required for efficient transcription by RNA polymerase I, and more specifically the polymerase I transcription termination step. Regulates negatively DNA replication. Not only involved in transcription-related chromatin-remodeling, but also required to maintain a specific chromatin configuration across the genome. Is also associated with histone deacetylase (HDAC) activity. Required for the bridging of SNF2, the FACT complex, the PAF complex as well as the U2 snRNP complex to H3K4me3. Functions to modulate the efficiency of pre-mRNA splicing in part through physical bridging of spliceosomal components to H3K4me3. Required for maintaining open chromatin and pluripotency in embryonic stem cells.
• Tissue Specificity: Expressed in many tissues including in the brain, where the highest level of expression is found in the cerebellum and basal ganglia.
• Reactome Pathway: Estrogen-dependent gene expression (R-HSA-9018519)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephrolithiasis, calcium oxalate	DIS5J79C	Definitive	Genetic Variation	[1]
Xeroderma pigmentosum group C	DIS8DQXS	Definitive	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Genetic Variation	[3]
Adult lymphoma	DISK8IZR	Strong	Genetic Variation	[4]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[5]
Alzheimer disease	DISF8S70	Strong	Biomarker	[6]
Alzheimer disease 3	DISVT69G	Strong	Biomarker	[6]
Colon cancer	DISVC52G	Strong	Genetic Variation	[7]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[7]
Colorectal adenoma	DISTSVHM	Strong	Genetic Variation	[7]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[7]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[7]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[7]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[7]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[7]
Gastric cancer	DISXGOUK	Strong	Genetic Variation	[8]
Glioma	DIS5RPEH	Strong	Altered Expression	[9]
leukaemia	DISS7D1V	Strong	Genetic Variation	[4]
Leukemia	DISNAKFL	Strong	Genetic Variation	[4]
Lymphoma	DISN6V4S	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[10]
Pediatric lymphoma	DIS51BK2	Strong	Genetic Variation	[4]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[11]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[12]
Stomach cancer	DISKIJSX	Strong	Genetic Variation	[8]
Carcinoma	DISH9F1N	moderate	Biomarker	[13]
Pilarowski-Bjornsson syndrome	DIS1OMWG	Supportive	Autosomal dominant	[14]
Breast cancer	DIS7DPX1	Limited	Posttranslational Modification	[15]
Breast carcinoma	DIS2UE88	Limited	Posttranslational Modification	[15]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[16]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[13]
Prostate cancer	DISF190Y	Limited	Genetic Variation	[11]

5 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[27]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[28]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[29]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[28]

12 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 Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[18]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[20]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[21]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[22]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[23]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[24]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[25]
Indomethacin	DMSC4A7	Approved	Indomethacin decreases the expression of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[26]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[30]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Chromodomain-helicase-DNA-binding protein 1 (CHD1).	[31]

References

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• [2] Chromatin remodeler CHD1 promotes XPC-to-TFIIH handover of nucleosomal UV lesions in nucleotide excision repair.EMBO J. 2017 Nov 15;36(22):3372-3386. doi: 10.15252/embj.201695742. Epub 2017 Oct 10.
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• [4] Congenital heart disease complexity and childhood cancer risk.Birth Defects Res. 2018 Oct 16;110(17):1314-1321. doi: 10.1002/bdr2.1390. Epub 2018 Oct 16.
• [5] Sequencing of prostate cancers identifies new cancer genes, routes of progression and drug targets.Nat Genet. 2018 May;50(5):682-692. doi: 10.1038/s41588-018-0086-z. Epub 2018 Apr 16.
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• [8] Single nucleotide polymorphisms (SNPs) at CDH1 promoter region in familial gastric cancer.Rev Esp Enferm Dig. 2006 Jan;98(1):36-41. doi: 10.4321/s1130-01082006000100005.
• [9] MATN1-AS1 promotes glioma progression by functioning as ceRNA of miR-200b/c/429 to regulate CHD1 expression.Cell Prolif. 2020 Jan;53(1):e12700. doi: 10.1111/cpr.12700. Epub 2019 Oct 30.
• [10] Comparison of CDH1 Gene Hypermethylation Status in Blood and Serum among Gastric Cancer Patients.Pathol Oncol Res. 2020 Apr;26(2):1057-1062. doi: 10.1007/s12253-019-00658-5. Epub 2019 Apr 15.
• [11] CHD1 Loss Alters AR Binding at Lineage-Specific Enhancers and Modulates Distinct Transcriptional Programs to Drive Prostate Tumorigenesis.Cancer Cell. 2019 Apr 15;35(4):603-617.e8. doi: 10.1016/j.ccell.2019.03.001. Epub 2019 Mar 28.
• [12] The long tail of oncogenic drivers in prostate cancer.Nat Genet. 2018 May;50(5):645-651. doi: 10.1038/s41588-018-0078-z. Epub 2018 Apr 2.
• [13] Prostatic adenocarcinoma CNS parenchymal and dural metastases: alterations in ERG, CHD1 and MAP3K7 expression.J Neurooncol. 2019 Apr;142(2):319-325. doi: 10.1007/s11060-019-03099-x. Epub 2019 Jan 17.
• [14] Missense variants in the chromatin remodeler CHD1 are associated with neurodevelopmental disability. J Med Genet. 2018 Aug;55(8):561-566. doi: 10.1136/jmedgenet-2017-104759. Epub 2017 Sep 2.
• [15] Aberrant promoter methylation of the CHD1 gene may contribute to the pathogenesis of breast cancer: a meta-analysis.Tumour Biol. 2014 Sep;35(9):9395-404. doi: 10.1007/s13277-014-2235-z. Epub 2014 Jun 22.
• [16] SPOP-Mutated/CHD1-Deleted Lethal Prostate Cancer and Abiraterone Sensitivity.Clin Cancer Res. 2018 Nov 15;24(22):5585-5593. doi: 10.1158/1078-0432.CCR-18-0937. Epub 2018 Aug 1.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [22] 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.
• [23] 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.
• [24] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [25] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [26] Mechanisms of indomethacin-induced alterations in the choline phospholipid metabolism of breast cancer cells. Neoplasia. 2006 Sep;8(9):758-71.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [31] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.