Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7CZK7C)

• DOT Name: Chromodomain-helicase-DNA-binding protein 1-like (CHD1L)
• Synonyms: EC 3.6.4.-; Amplified in liver cancer protein 1
• Gene Name: CHD1L
• Related Disease:
  Adenocarcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Carcinoma of esophagus
  Carcinoma of liver and intrahepatic biliary tract
  Cholangiocarcinoma
  Cholelithiasis
  Chromosomal disorder
  Colorectal carcinoma
  Congenital heart disease
  Drug dependence
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Hypertrophic cardiomyopathy
  Liver cancer
  Lung adenocarcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Neoplasm of esophagus
  Pancreatic cancer
  Plasma cell myeloma
  Renal dysplasia, bilateral
  Squamous cell carcinoma
  Substance abuse
  Substance dependence
  Coronary atherosclerosis
  Coronary heart disease
  Intrahepatic cholangiocarcinoma
  Tetralogy of fallot
  Congenital anomaly of kidney and urinary tract
  Invasive ductal breast carcinoma
  Non-small-cell lung cancer
• UniProt ID: CHD1L_HUMAN
• PDB ID: 6ZHX; 6ZHY; 7ENN; 7EPU; 7OTQ; 8B0A
• EC Number: 3.6.4.-
• Pfam ID: PF00271 ; PF00176
• Sequence:
  MERAGATSRGGQAPGFLLRLHTEGRAEAARVQEQDLRQWGLTGIHLRSYQLEGVNWLAQR
  FHCQNGCILGDEMGLGKTCQTIALFIYLAGRLNDEGPFLILCPLSVLSNWKEEMQRFAPG
  LSCVTYAGDKEERACLQQDLKQESRFHVLLTTYEICLKDASFLKSFPWSVLVVDEAHRLK
  NQSSLLHKTLSEFSVVFSLLLTGTPIQNSLQELYSLLSFVEPDLFSKEEVGDFIQRYQDI
  EKESESASELHKLLQPFLLRRVKAEVATELPKKTEVVIYHGMSALQKKYYKAILMKDLDA
  FENETAKKVKLQNILSQLRKCVDHPYLFDGVEPEPFEVGDHLTEASGKLHLLDKLLAFLY
  SGGHRVLLFSQMTQMLDILQDYMDYRGYSYERVDGSVRGEERHLAIKNFGQQPIFVFLLS
  TRAGGVGMNLTAADTVIFVDSDFNPQNDLQAAARAHRIGQNKSVKVIRLIGRDTVEEIVY
  RKAASKLQLTNMIIEGGHFTLGAQKPAADADLQLSEILKFGLDKLLASEGSTMDEIDLES
  ILGETKDGQWVSDALPAAEGGSRDQEEGKNHMYLFEGKDYSKEPSKEDRKSFEQLVNLQK
  TLLEKASQEGRSLRNKGSVLIPGLVEGSTKRKRVLSPEELEDRQKKRQEAAAKRRRLIEE
  KKRQKEEAEHKKKMAWWESNNYQSFCLPSEESEPEDLENGEESSAELDYQDPDATSLKYV
  SGDVTHPQAGAEDALIVHCVDDSGHWGRGGLFTALEKRSAEPRKIYELAGKMKDLSLGGV
  LLFPVDDKESRNKGQDLLALIVAQHRDRSNVLSGIKMAALEEGLKKIFLAAKKKKASVHL
  PRIGHATKGFNWYGTERLIRKHLAARGIPTYIYYFPRSKSAVLHSQSSSSSSRQLVP
• Function: ATP-dependent chromatin remodeler that mediates chromatin-remodeling following DNA damage. Recruited to DNA damage sites through interaction with poly-ADP-ribose: specifically recognizes and binds histones that are poly-ADP-ribosylated on serine residues in response to DNA damage. Poly-ADP-ribose-binding activates the ATP-dependent chromatin remodeler activity, thereby regulating chromatin during DNA repair. Catalyzes nucleosome sliding away from DNA breaks in an ATP-dependent manner. Chromatin remodeling activity promotes PARP2 removal from chromatin.
• Tissue Specificity: Frequently overexpressed in hepatomacellular carcinomas.
• Reactome Pathway:
  Dual Incision in GG-NER (R-HSA-5696400)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[4]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[2]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[2]
Cholelithiasis	DISERLZB	Strong	Altered Expression	[2]
Chromosomal disorder	DISM5BB5	Strong	Biomarker	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[6]
Congenital heart disease	DISQBA23	Strong	Altered Expression	[7]
Drug dependence	DIS9IXRC	Strong	Biomarker	[8]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[4]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[9]
Hypertrophic cardiomyopathy	DISQG2AI	Strong	Biomarker	[7]
Liver cancer	DISDE4BI	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[1]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[4]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[10]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[11]
Renal dysplasia, bilateral	DIS27M3V	Strong	Genetic Variation	[12]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[1]
Substance abuse	DIS327VW	Strong	Biomarker	[8]
Substance dependence	DISDRAAR	Strong	Biomarker	[8]
Coronary atherosclerosis	DISKNDYU	moderate	Altered Expression	[13]
Coronary heart disease	DIS5OIP1	moderate	Altered Expression	[13]
Intrahepatic cholangiocarcinoma	DIS6GOC8	moderate	Biomarker	[14]
Tetralogy of fallot	DISMHFNW	moderate	Biomarker	[15]
Congenital anomaly of kidney and urinary tract	DIS84IVH	Limited	Autosomal dominant	[16]
Invasive ductal breast carcinoma	DIS43J58	Limited	Altered Expression	[17]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[19]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[21]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[22]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[28]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[29]
BRN-3548355	DM4KXT0	Investigative	BRN-3548355 increases the expression of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[30]

3 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 affects the methylation of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[24]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[25]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Chromodomain-helicase-DNA-binding protein 1-like (CHD1L).	[27]

References

• [1] Overexpression of CHD1L is positively associated with metastasis of lung adenocarcinoma and predicts patients poor survival.Oncotarget. 2015 Oct 13;6(31):31181-90. doi: 10.18632/oncotarget.5070.
• [2] Clinical significance of chromodomain helicase/ATPase DNA binding protein 1-like and human mutL homolog 1 gene expression in cholangiocarcinoma.Oncol Lett. 2018 Sep;16(3):2989-2994. doi: 10.3892/ol.2018.9043. Epub 2018 Jun 28.
• [3] CHD1L promotes cell cycle progression and cell motility by up-regulating MDM2 in breast cancer.Am J Transl Res. 2019 Mar 15;11(3):1581-1592. eCollection 2019.
• [4] ALC1 knockdown enhances cisplatin cytotoxicity of esophageal squamous cell carcinoma cells by inhibition of glycolysis through PI3K/Akt pathway.Life Sci. 2019 Sep 1;232:116679. doi: 10.1016/j.lfs.2019.116679. Epub 2019 Jul 21.
• [5] Chromatin remodeler ALC1 prevents replication-fork collapse by slowing fork progression.PLoS One. 2018 Feb 6;13(2):e0192421. doi: 10.1371/journal.pone.0192421. eCollection 2018.
• [6] CHD1L promotes tumor progression and predicts survival in colorectal carcinoma.J Surg Res. 2013 Nov;185(1):84-91. doi: 10.1016/j.jss.2013.05.008. Epub 2013 May 25.
• [7] Human atrial myosin light chain 1 expression attenuates heart failure.Adv Exp Med Biol. 2005;565:283-92; discussion 92, 405-15. doi: 10.1007/0-387-24990-7_21.
• [8] Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
• [9] CHD1L contributes to cisplatin resistance by upregulating the ABCB1-NF-B axis in human non-small-cell lung cancer.Cell Death Dis. 2019 Feb 4;10(2):99. doi: 10.1038/s41419-019-1371-1.
• [10] CHD1L Expression Increases Tumor Progression and Acts as a Predictive Biomarker for Poor Prognosis in Pancreatic Cancer.Dig Dis Sci. 2017 Sep;62(9):2376-2385. doi: 10.1007/s10620-017-4641-8. Epub 2017 Jun 23.
• [11] Cell adhesion induces overexpression of chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) and contributes to cell adhesion-mediated drug resistance (CAM-DR) in multiple myeloma cells.Leuk Res. 2016 Aug;47:54-62. doi: 10.1016/j.leukres.2016.05.007. Epub 2016 May 12.
• [12] Detection of a familial 1q21.1 microdeletion and concomitant CHD1L mutation in a fetus with oligohydramnios and bilateral renal dysplasia on prenatal ultrasound.Taiwan J Obstet Gynecol. 2019 Nov;58(6):859-863. doi: 10.1016/j.tjog.2019.07.031.
• [13] Hypercholesterolemia and hyper-alpha-lipoproteinemia in schoolchildren.Pediatrics. 1978 Oct;62(4):478-87.
• [14] [Corrigendum] CHD1L is associated with poor survival and promotes the proliferation and metastasis of intrahepatic cholangiocarcinoma.Oncol Rep. 2019 Oct;42(4):1631. doi: 10.3892/or.2019.7262. Epub 2019 Aug 5.
• [15] Remodeling of the hypertrophied human myocardium by cardiac bHLH transcription factors.J Cell Biochem. 1999 Sep 15;74(4):551-61. doi: 10.1002/(sici)1097-4644(19990915)74:4<551::aid-jcb5>3.3.co;2-0.
• [16] 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.
• [17] Chromodomain Helicase/ATPase DNA-Binding Protein 1-Like Gene (CHD1L) Expression and Implications for Invasion and Metastasis of Breast Cancer.PLoS One. 2015 Nov 23;10(11):e0143030. doi: 10.1371/journal.pone.0143030. eCollection 2015.
• [18] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [19] 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.
• [20] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [21] 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.
• [22] 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.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [29] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [30] Gene expression profiles in HPV-immortalized human cervical cells treated with the nicotine-derived carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Chem Biol Interact. 2009 Feb 12;177(3):173-80. doi: 10.1016/j.cbi.2008.10.051. Epub 2008 Nov 6.