Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6E6E8P)

• DOT Name: Neural cell adhesion molecule L1-like protein (CHL1)
• Synonyms: Close homolog of L1
• Gene Name: CHL1
• Related Disease:
  Intellectual disability
  Adenocarcinoma
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Androgen insensitivity syndrome
  Angiomyolipoma
  Bipolar disorder
  Breast neoplasm
  Colorectal carcinoma
  Depression
  Endometrial cancer
  Endometrial carcinoma
  Epilepsy
  Glioblastoma multiforme
  Glioma
  Kidney cancer
  Large cell carcinoma
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Lung squamous cell carcinoma
  Neoplasm
  Neuroblastoma
  Non-small-cell lung cancer
  Pituitary adenoma
  Renal carcinoma
  Schizophrenia
  Squamous cell carcinoma
  Autism
  Nasopharyngeal carcinoma
  Asthma
  Breast cancer
  Breast carcinoma
  Cognitive impairment
  Hepatocellular carcinoma
  Melanoma
  Thyroid gland papillary carcinoma
• UniProt ID: NCHL1_HUMAN
• Pfam ID: PF13882 ; PF00041 ; PF07679 ; PF00047 ; PF13927
• Sequence:
  MEPLLLGRGLIVYLMFLLLKFSKAIEIPSSVQQVPTIIKQSKVQVAFPFDEYFQIECEAK
  GNPEPTFSWTKDGNPFYFTDHRIIPSNNSGTFRIPNEGHISHFQGKYRCFASNKLGIAMS
  EEIEFIVPSVPKFPKEKIDPLEVEEGDPIVLPCNPPKGLPPLHIYWMNIELEHIEQDERV
  YMSQKGDLYFANVEEKDSRNDYCCFAAFPRLRTIVQKMPMKLTVNSSNSIKQRKPKLLLP
  PTESGSESSITILKGEILLLECFAEGLPTPQVDWNKIGGDLPKGRETKENYGKTLKIENV
  SYQDKGNYRCTASNFLGTATHDFHVIVEEPPRWTKKPQSAVYSTGSNGILLCEAEGEPQP
  TIKWRVNGSPVDNHPFAGDVVFPREISFTNLQPNHTAVYQCEASNVHGTILANANIDVVD
  VRPLIQTKDGENYATVVGYSAFLHCEFFASPEAVVSWQKVEEVKPLEGRRYHIYENGTLQ
  INRTTEEDAGSYSCWVENAIGKTAVTANLDIRNATKLRVSPKNPRIPKLHMLELHCESKC
  DSHLKHSLKLSWSKDGEAFEINGTEDGRIIIDGANLTISNVTLEDQGIYCCSAHTALDSA
  ADITQVTVLDVPDPPENLHLSERQNRSVRLTWEAGADHNSNISEYIVEFEGNKEEPGRWE
  ELTRVQGKKTTVILPLAPFVRYQFRVIAVNEVGRSQPSQPSDHHETPPAAPDRNPQNIRV
  QASQPKEMIIKWEPLKSMEQNGPGLEYRVTWKPQGAPVEWEEETVTNHTLRVMTPAVYAP
  YDVKVQAINQLGSGPDPQSVTLYSGEDYPDTAPVIHGVDVINSTLVKVTWSTVPKDRVHG
  RLKGYQINWWKTKSLLDGRTHPKEVNILRFSGQRNSGMVPSLDAFSEFHLTVLAYNSKGA
  GPESEPYIFQTPEGVPEQPTFLKVIKVDKDTATLSWGLPKKLNGNLTGYLLQYQIINDTY
  EIGELNDINITTPSKPSWHLSNLNATTKYKFYLRACTSQGCGKPITEESSTLGEGSKGIG
  KISGVNLTQKTHPIEVFEPGAEHIVRLMTKNWGDNDSIFQDVIETRGREYAGLYDDISTQ
  GWFIGLMCAIALLTLLLLTVCFVKRNRGGKYSVKEKEDLHPDPEIQSVKDETFGEYSDSD
  EKPLKGSLRSLNRDMQPTESADSLVEYGEGDHGLFSEDGSFIGAYAGSKEKGSVESNGSS
  TATFPLRA
• Function: Extracellular matrix and cell adhesion protein that plays a role in nervous system development and in synaptic plasticity. Both soluble and membranous forms promote neurite outgrowth of cerebellar and hippocampal neurons and suppress neuronal cell death. Plays a role in neuronal positioning of pyramidal neurons and in regulation of both the number of interneurons and the efficacy of GABAergic synapses. May play a role in regulating cell migration in nerve regeneration and cortical development. Potentiates integrin-dependent cell migration towards extracellular matrix proteins. Recruits ANK3 to the plasma membrane.
• Tissue Specificity: Expressed in the fetal and adult brain as well as in Schwann cell culture. Also detected in adult peripheral tissues.
• Reactome Pathway: CHL1 interactions (R-HSA-447041)

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Intellectual disability	DISMBNXP	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Biomarker	[5]
Androgen insensitivity syndrome	DISUZBBO	Strong	Genetic Variation	[6]
Angiomyolipoma	DIS2L71N	Strong	Altered Expression	[7]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[8]
Breast neoplasm	DISNGJLM	Strong	Posttranslational Modification	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Depression	DIS3XJ69	Strong	Altered Expression	[11]
Endometrial cancer	DISW0LMR	Strong	Biomarker	[12]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[12]
Epilepsy	DISBB28L	Strong	Genetic Variation	[1]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Kidney cancer	DISBIPKM	Strong	Biomarker	[13]
Large cell carcinoma	DISYMCOF	Strong	Altered Expression	[2]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[2]
Lung cancer	DISCM4YA	Strong	Biomarker	[4]
Lung carcinoma	DISTR26C	Strong	Biomarker	[4]
Lung neoplasm	DISVARNB	Strong	Biomarker	[14]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[15]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[2]
Pituitary adenoma	DISJ5R1X	Strong	Altered Expression	[16]
Renal carcinoma	DISER9XT	Strong	Biomarker	[13]
Schizophrenia	DISSRV2N	Strong	Biomarker	[17]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[2]
Autism	DISV4V1Z	moderate	Altered Expression	[18]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[19]
Asthma	DISW9QNS	Limited	Genetic Variation	[20]
Breast cancer	DIS7DPX1	Limited	Posttranslational Modification	[9]
Breast carcinoma	DIS2UE88	Limited	Posttranslational Modification	[9]
Cognitive impairment	DISH2ERD	Limited	Altered Expression	[21]
Hepatocellular carcinoma	DIS0J828	Limited	Altered Expression	[22]
Melanoma	DIS1RRCY	Limited	Biomarker	[23]
Thyroid gland papillary carcinoma	DIS48YMM	Limited	Biomarker	[24]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Paroxetine	DM5PVQE	Approved	Neural cell adhesion molecule L1-like protein (CHL1) affects the response to substance of Paroxetine.	[18]

6 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 Neural cell adhesion molecule L1-like protein (CHL1).	[25]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Neural cell adhesion molecule L1-like protein (CHL1).	[26]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Neural cell adhesion molecule L1-like protein (CHL1).	[27]
Amphotericin B	DMTAJQE	Approved	Amphotericin B decreases the expression of Neural cell adhesion molecule L1-like protein (CHL1).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Neural cell adhesion molecule L1-like protein (CHL1).	[30]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Neural cell adhesion molecule L1-like protein (CHL1).	[31]

1 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 Neural cell adhesion molecule L1-like protein (CHL1).	[29]

References

• [1] Microduplication of 3p26.3 in nonsyndromic intellectual disability indicates an important role of CHL1 for normal cognitive function.Neuropediatrics. 2013 Oct;44(5):268-71. doi: 10.1055/s-0033-1333874. Epub 2013 Feb 22.
• [2] Protein expression of close homologue of L1 (CHL1) is a marker for overall survival in non-small cell lung cancer (NSCLC).J Cancer Res Clin Oncol. 2019 Sep;145(9):2285-2292. doi: 10.1007/s00432-019-02989-x. Epub 2019 Aug 1.
• [3] CHL1 Is Expressed and Functions as a Malignancy Promoter in Glioma Cells.Front Mol Neurosci. 2017 Oct 17;10:324. doi: 10.3389/fnmol.2017.00324. eCollection 2017.
• [4] CHL1 gene polymorphisms increase lung cancer susceptibility.Oncotarget. 2018 Jan 6;9(17):13545-13550. doi: 10.18632/oncotarget.24057. eCollection 2018 Mar 2.
• [5] Genome-wide association study for variants that modulate relationships between cerebrospinal fluid amyloid-beta 42, tau, and p-tau levels.Alzheimers Res Ther. 2018 Aug 28;10(1):86. doi: 10.1186/s13195-018-0410-y.
• [6] Lack of association between the CHL1 gene and adolescent idiopathic scoliosis susceptibility in Han Chinese: a case-control study.BMC Musculoskelet Disord. 2014 Feb 10;15:38. doi: 10.1186/1471-2474-15-38.
• [7] Expression of the neural stem cell markers NG2 and L1 in human angiomyolipoma: are angiomyolipomas neoplasms of stem cells?.Mol Med. 2007 Mar-Apr;13(3-4):160-5. doi: 10.2119/2006?0070.Lim.
• [8] Neuroplasticity, Neurotransmission and Brain-Related Genes in Major Depression and Bipolar Disorder: Focus on Treatment Outcomes in an Asiatic Sample.Adv Ther. 2018 Oct;35(10):1656-1670. doi: 10.1007/s12325-018-0781-2. Epub 2018 Sep 3.
• [9] CHL1 hypermethylation as a potential biomarker of poor prognosis in breast cancer.Oncotarget. 2017 Feb 28;8(9):15789-15801. doi: 10.18632/oncotarget.15004.
• [10] Aberrant DNA Methylation: Implications in Racial Health Disparity.PLoS One. 2016 Apr 25;11(4):e0153125. doi: 10.1371/journal.pone.0153125. eCollection 2016.
• [11] CHL1, ITGB3 and SLC6A4 gene expression and antidepressant drug response: results from the Munich Antidepressant Response Signature (MARS) study.Pharmacogenomics. 2015;16(7):689-701. doi: 10.2217/pgs.15.31. Epub 2015 May 6.
• [12] Long noncoding RNA CHL1-AS1 promotes cell proliferation and migration by sponging miR-6076 to regulate CHL1 expression in endometrial cancer.J Cell Biochem. 2020 Mar;121(3):2655-2663. doi: 10.1002/jcb.29486. Epub 2019 Nov 17.
• [13] Differential expression of CHL1 gene during development of major human cancers.PLoS One. 2011 Mar 7;6(3):e15612. doi: 10.1371/journal.pone.0015612.
• [14] Tumor-dependent secretion of close homolog of L1 results in elevation of its circulating level in mouse model for human lung tumor.Biochem Biophys Res Commun. 2018 Jul 2;501(4):982-987. doi: 10.1016/j.bbrc.2018.05.096. Epub 2018 May 22.
• [15] CHL1 gene acts as a tumor suppressor in human neuroblastoma.Oncotarget. 2018 May 25;9(40):25903-25921. doi: 10.18632/oncotarget.25403. eCollection 2018 May 25.
• [16] Towards an integrated molecular and clinical strategy to predict early recurrence in surgically resected non-functional pituitary adenomas.J Clin Neurosci. 2012 Nov;19(11):1535-40. doi: 10.1016/j.jocn.2012.01.038. Epub 2012 Sep 17.
• [17] Increased temporal discounting after chronic stress in CHL1-deficient mice is reversed by 5-HT2C agonist Ro 60-0175.Neuroscience. 2017 Aug 15;357:110-118. doi: 10.1016/j.neuroscience.2017.05.047. Epub 2017 Jun 3.
• [18] Genome-wide expression profiling of human lymphoblastoid cell lines identifies CHL1 as a putative SSRI antidepressant response biomarker. Pharmacogenomics. 2011 Feb;12(2):171-84. doi: 10.2217/pgs.10.185.
• [19] Tumor suppressor genes on frequently deleted chromosome 3p in nasopharyngeal carcinoma.Chin J Cancer. 2012 May;31(5):215-22. doi: 10.5732/cjc.011.10364. Epub 2012 Feb 24.
• [20] Sequence variant analysis of RNA sequences in severe equine asthma.PeerJ. 2018 Oct 11;6:e5759. doi: 10.7717/peerj.5759. eCollection 2018.
• [21] CALL interrupted in a patient with non-specific mental retardation: gene dosage-dependent alteration of murine brain development and behavior.Hum Mol Genet. 2003 Jul 1;12(13):1463-74. doi: 10.1093/hmg/ddg165.
• [22] CHL1 expression differentiates Hrthle cell carcinoma from benign Hrthle cell nodules.J Surg Oncol. 2018 Nov;118(6):1042-1049. doi: 10.1002/jso.25214. Epub 2018 Oct 12.
• [23] Targeting negative regulation of p53 by MDM2 and WIP1 as a therapeutic strategy in cutaneous melanoma.Br J Cancer. 2018 Feb 20;118(4):495-508. doi: 10.1038/bjc.2017.433. Epub 2017 Dec 12.
• [24] miR-182 targets CHL1 and controls tumor growth and invasion in papillary thyroid carcinoma.Biochem Biophys Res Commun. 2014 Jul 18;450(1):857-62. doi: 10.1016/j.bbrc.2014.06.073. Epub 2014 Jun 24.
• [25] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [26] 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.
• [27] 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.
• [28] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [29] 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.
• [30] 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.
• [31] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [32] Genome-wide expression profiling of human lymphoblastoid cell lines identifies CHL1 as a putative SSRI antidepressant response biomarker. Pharmacogenomics. 2011 Feb;12(2):171-84. doi: 10.2217/pgs.10.185.