Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1MJ51D)

• DOT Name: Hepatic and glial cell adhesion molecule (HEPACAM)
• Synonyms: glialCAM; Hepatocyte cell adhesion molecule; Protein hepaCAM
• Gene Name: HEPACAM
• Related Disease:
  Megalencephalic leukoencephalopathy with subcortical cysts 2A
  Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability
  Adult glioblastoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Hereditary nonpolyposis colon cancer
  Lynch syndrome
  Neoplasm
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Renal carcinoma
  Transitional cell carcinoma
  Urothelial carcinoma
  Autism spectrum disorder
  Macrocephaly-autism syndrome
  Megalencephalic leukoencephalopathy with subcortical cysts
  Advanced cancer
  Autism
  Castration-resistant prostate carcinoma
  Intellectual disability
  Leukodystrophy
  Renal cell carcinoma
• UniProt ID: HECAM_HUMAN
• PDB ID: 7UQC
• Pfam ID: PF13927 ; PF07686
• Sequence:
  MKRERGALSRASRALRLAPFVYLLLIQTDPLEGVNITSPVRLIHGTVGKSALLSVQYSST
  SSDRPVVKWQLKRDKPVTVVQSIGTEVIGTLRPDYRDRIRLFENGSLLLSDLQLADEGTY
  EVEISITDDTFTGEKTINLTVDVPISRPQVLVASTTVLELSEAFTLNCSHENGTKPSYTW
  LKDGKPLLNDSRMLLSPDQKVLTITRVLMEDDDLYSCMVENPISQGRSLPVKITVYRRSS
  LYIILSTGGIFLLVTLVTVCACWKPSKRKQKKLEKQNSLEYMDQNDDRLKPEADTLPRSG
  EQERKNPMALYILKDKDSPETEENPAPEPRSATEPGPPGYSVSPAVPGRSPGLPIRSARR
  YPRSPARSPATGRTHSSPPRAPSSPGRSRSASRTLRTAGVHIIREQDEAGPVEISA
• Function: Involved in regulating cell motility and cell-matrix interactions. May inhibit cell growth through suppression of cell proliferation.

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Megalencephalic leukoencephalopathy with subcortical cysts 2A	DISK3ULI	Definitive	Autosomal recessive	[1]
Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability	DISTSA5L	Definitive	Autosomal dominant	[1]
Adult glioblastoma	DISVP4LU	Strong	Altered Expression	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[5]
Hereditary nonpolyposis colon cancer	DISPA49R	Strong	Biomarker	[6]
Lynch syndrome	DIS3IW5F	Strong	Biomarker	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[8]
Prostate cancer	DISF190Y	Strong	Altered Expression	[7]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[7]
Renal carcinoma	DISER9XT	Strong	Altered Expression	[9]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[10]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[10]
Autism spectrum disorder	DISXK8NV	moderate	Genetic Variation	[11]
Macrocephaly-autism syndrome	DISPGWOW	Supportive	Autosomal dominant	[12]
Megalencephalic leukoencephalopathy with subcortical cysts	DISK9A1M	Supportive	Autosomal dominant	[13]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[3]
Autism	DISV4V1Z	Limited	Biomarker	[14]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Altered Expression	[15]
Intellectual disability	DISMBNXP	Limited	Biomarker	[14]
Leukodystrophy	DISVY1TT	Limited	Biomarker	[16]
Renal cell carcinoma	DISQZ2X8	Limited	Altered Expression	[3]

4 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 Hepatic and glial cell adhesion molecule (HEPACAM).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Hepatic and glial cell adhesion molecule (HEPACAM).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Hepatic and glial cell adhesion molecule (HEPACAM).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Hepatic and glial cell adhesion molecule (HEPACAM).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Hepatic and glial cell adhesion molecule (HEPACAM).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Hepatic and glial cell adhesion molecule (HEPACAM).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Hepatic and glial cell adhesion molecule (HEPACAM).	[19]
Marinol	DM70IK5	Approved	Marinol increases the expression of Hepatic and glial cell adhesion molecule (HEPACAM).	[20]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Hepatic and glial cell adhesion molecule (HEPACAM).	[21]

References

• [1] 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.
• [2] The immunoglobulin-like cell adhesion molecule hepaCAM induces differentiation of human glioblastoma U373-MG cells.J Cell Biochem. 2009 Aug 15;107(6):1129-38. doi: 10.1002/jcb.22215.
• [3] HepaCAM Regulates Warburg Effect of Renal Cell Carcinoma via HIF-1/NF-B Signaling Pathway.Urology. 2019 May;127:61-67. doi: 10.1016/j.urology.2018.11.033. Epub 2018 Dec 4.
• [4] Overexpression of Hepatocyte Cell Adhesion Molecule (hepaCAM) Inhibits the Proliferation, Migration, and Invasion in Colorectal Cancer Cells.Oncol Res. 2017 Aug 7;25(7):1039-1046. doi: 10.3727/096504016X14813914187138. Epub 2016 Dec 15.
• [5] Expression of hepaCAM is downregulated in cancers and induces senescence-like growth arrest via a p53/p21-dependent pathway in human breast cancer cells.Carcinogenesis. 2008 Dec;29(12):2298-305. doi: 10.1093/carcin/bgn226. Epub 2008 Oct 8.
• [6] Advances in the study of Lynch syndrome in China.World J Gastroenterol. 2015 Jun 14;21(22):6861-71. doi: 10.3748/wjg.v21.i22.6861.
• [7] HepaCAM inhibits cell proliferation and invasion in prostate cancer by suppressing nuclear translocation of the androgen receptor via its cytoplasmic domain.Mol Med Rep. 2019 Mar;19(3):2115-2124. doi: 10.3892/mmr.2019.9841. Epub 2019 Jan 10.
• [8] HEPACAM inhibited the growth and migration of cancer cells in the progression of non-small cell lung cancer.Tumour Biol. 2016 Feb;37(2):2621-7. doi: 10.1007/s13277-015-4084-9. Epub 2015 Sep 22.
• [9] Renal tumor-derived exosomes inhibit hepaCAM expression of renal carcinoma cells in a p-AKT-dependent manner.Neoplasma. 2014;61(4):416-23. doi: 10.4149/neo_2014_051.
• [10] Expression and clinical significance of hepaCAM and VEGF in urothelial carcinoma.World J Urol. 2010 Aug;28(4):473-8. doi: 10.1007/s00345-010-0573-z. Epub 2010 Jul 1.
• [11] Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations. Hum Mutat. 2019 Jun;40(6):801-815. doi: 10.1002/humu.23724. Epub 2019 Apr 29.
• [12] Mutant GlialCAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. Am J Hum Genet. 2011 Apr 8;88(4):422-32. doi: 10.1016/j.ajhg.2011.02.009. Epub 2011 Mar 17.
• [13] Megalencephalic Leukoencephalopathy with Subcortical Cysts. 2003 Aug 11 [updated 2023 Jul 27]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [14] Megalencephalic leukoencephalopathy with subcortical cysts: Characterization of disease variants.Neurology. 2018 Apr 17;90(16):e1395-e1403. doi: 10.1212/WNL.0000000000005334. Epub 2018 Mar 21.
• [15] HepaCAM inhibits the malignant behavior of castration-resistant prostate cancer cells by downregulating Notch signaling and PF-3084014 (a -secretase inhibitor) partly reverses the resistance of refractory prostate cancer to docetaxel and enzalutamide in vitro.Int J Oncol. 2018 Jul;53(1):99-112. doi: 10.3892/ijo.2018.4370. Epub 2018 Apr 12.
• [16] Leukoencephalopathy-causing CLCN2 mutations are associated with impaired Cl(-) channel function and trafficking.J Physiol. 2017 Nov 15;595(22):6993-7008. doi: 10.1113/JP275087. Epub 2017 Oct 9.
• [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] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [20] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] 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.
• [23] 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.
• [24] 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.