Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT76CM19)

• DOT Name: HLA class I histocompatibility antigen, alpha chain F (HLA-F)
• Synonyms: CDA12; HLA F antigen; Leukocyte antigen F; MHC class I antigen F
• Gene Name: HLA-F
• Related Disease:
  Advanced cancer
  Behcet disease
  Bladder cancer
  Colon cancer
  Colorectal adenocarcinoma
  Colorectal cancer
  Colorectal cancer, susceptibility to, 1
  Colorectal cancer, susceptibility to, 10
  Colorectal cancer, susceptibility to, 12
  Colorectal carcinoma
  Colorectal neoplasm
  Epilepsy, idiopathic generalized
  Esophageal squamous cell carcinoma
  Gastric cancer
  Glioblastoma multiforme
  Glioma
  Gonorrhea
  Hemochromatosis
  Hepatitis B virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  HIV infectious disease
  Melanoma
  Multiple sclerosis
  Narcolepsy
  Neoplasm
  Stomach cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
  Vitiligo
  Autoimmune disease
  Juvenile myoclonic epilepsy
  Nasopharyngeal carcinoma
  Amyotrophic lateral sclerosis
  Coronary heart disease
  Granular corneal dystrophy type II
  Hereditary hemochromatosis
  Psoriatic arthritis
• UniProt ID: HLAF_HUMAN
• PDB ID: 5IUE; 5KNM
• Pfam ID: PF07654 ; PF00129
• Sequence:
  MAPRSLLLLLSGALALTDTWAGSHSLRYFSTAVSRPGRGEPRYIAVEYVDDTQFLRFDSD
  AAIPRMEPREPWVEQEGPQYWEWTTGYAKANAQTDRVALRNLLRRYNQSEAGSHTLQGMN
  GCDMGPDGRLLRGYHQHAYDGKDYISLNEDLRSWTAADTVAQITQRFYEAEEYAEEFRTY
  LEGECLELLRRYLENGKETLQRADPPKAHVAHHPISDHEATLRCWALGFYPAEITLTWQR
  DGEEQTQDTELVETRPAGDGTFQKWAAVVVPPGEEQRYTCHVQHEGLPQPLILRWEQSPQ
  PTIPIVGIVAGLVVLGAVVTGAVVAAVMWRKKSSDRNRGSYSQAAV
• Function: Non-classical major histocompatibility class Ib molecule postulated to play a role in immune surveillance, immune tolerance and inflammation. Functions in two forms, as a heterotrimeric complex with B2M/beta-2 microglobulin and a peptide (peptide-bound HLA-F-B2M) and as an open conformer (OC) devoid of peptide and B2M (peptide-free OC). In complex with B2M, presents non-canonical self-peptides carrying post-translational modifications, particularly phosphorylated self-peptides. Peptide-bound HLA-F-B2M acts as a ligand for LILRB1 inhibitory receptor, a major player in maternal-fetal tolerance. Peptide-free OC acts as a ligand for KIR3DS1 and KIR3DL2 receptors. Upon interaction with activating KIR3DS1 receptor on NK cells, triggers NK cell degranulation and anti-viral cytokine production. Through interaction with KIR3DL2 receptor, inhibits NK and T cell effector functions. May interact with other MHC class I OCs to cross-present exogenous viral, tumor or minor histompatibility antigens to cytotoxic CD8+ T cells, triggering effector and memory responses. May play a role in inflammatory responses in the peripheral nervous system. Through interaction with KIR3DL2, may protect motor neurons from astrocyte-induced toxicity.
• Tissue Specificity: Expressed in resting B cells (at protein level). Expressed in secondary lymphoid organs rich in B and T cells such as the tonsils, spleen, and thymus (at protein level) . Expressed in the endothelial cells of the tonsils . Expressed on activated lymphoid cells including B cells, NK cells, CD4+ T cells and memory T cells (at protein level) . Expressed in motor neurons of spinal cord .
• KEGG Pathway:
  Endocytosis (hsa04144)
  Phagosome (hsa04145)
  Cellular senescence (hsa04218)
  Cell adhesion molecules (hsa04514)
  Antigen processing and presentation (hsa04612)
  Type I diabetes mellitus (hsa04940)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Human T-cell leukemia virus 1 infection (hsa05166)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Viral carcinogenesis (hsa05203)
  Autoimmune thyroid disease (hsa05320)
  Allograft rejection (hsa05330)
  Graft-versus-host disease (hsa05332)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  Endosomal/Vacuolar pathway (R-HSA-1236977)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)
  Interferon gamma signaling (R-HSA-877300)
  Interferon alpha/beta signaling (R-HSA-909733)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Antigen Presentation (R-HSA-983170)
  ER-Phagosome pathway (R-HSA-1236974)

Molecular Interaction Atlas (MIA) of This DOT

38 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Behcet disease	DISSYMBS	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Biomarker	[1]
Colon cancer	DISVC52G	Strong	Genetic Variation	[3]
Colorectal adenocarcinoma	DISPQOUB	Strong	Genetic Variation	[3]
Colorectal cancer	DISNH7P9	Strong	Genetic Variation	[3]
Colorectal cancer, susceptibility to, 1	DISZ794C	Strong	Genetic Variation	[3]
Colorectal cancer, susceptibility to, 10	DISQXMYM	Strong	Genetic Variation	[3]
Colorectal cancer, susceptibility to, 12	DIS4FXJX	Strong	Genetic Variation	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Colorectal neoplasm	DISR1UCN	Strong	Genetic Variation	[3]
Epilepsy, idiopathic generalized	DISODZC9	Strong	Genetic Variation	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[7]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[8]
Glioma	DIS5RPEH	Strong	Biomarker	[8]
Gonorrhea	DISQ5AO6	Strong	Altered Expression	[9]
Hemochromatosis	DISAPY0H	Strong	Genetic Variation	[10]
Hepatitis B virus infection	DISLQ2XY	Strong	Genetic Variation	[11]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[12]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[13]
HIV infectious disease	DISO97HC	Strong	Altered Expression	[14]
Melanoma	DIS1RRCY	Strong	Biomarker	[15]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[16]
Narcolepsy	DISLCNLI	Strong	Genetic Variation	[17]
Neoplasm	DISZKGEW	Strong	Altered Expression	[6]
Stomach cancer	DISKIJSX	Strong	Biomarker	[7]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[1]
Vitiligo	DISR05SL	Strong	Genetic Variation	[18]
Autoimmune disease	DISORMTM	moderate	Altered Expression	[19]
Juvenile myoclonic epilepsy	DISYXV1N	moderate	Genetic Variation	[20]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Genetic Variation	[21]
Amyotrophic lateral sclerosis	DISF7HVM	Limited	Biomarker	[22]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[23]
Granular corneal dystrophy type II	DISAEE20	Limited	Genetic Variation	[24]
Hereditary hemochromatosis	DISVG5MT	Limited	Biomarker	[25]
Psoriatic arthritis	DISLWTG2	Limited	Genetic Variation	[26]

27 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 HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[27]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[29]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[30]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[31]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[32]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[33]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[34]
Selenium	DM25CGV	Approved	Selenium decreases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[35]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[36]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[37]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[38]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[39]
Simvastatin	DM30SGU	Approved	Simvastatin affects the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[40]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[39]
Gefitinib	DM15F0X	Approved	Gefitinib affects the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[40]
Gentamicin	DMKINJO	Approved	Gentamicin increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[39]
Hydrochlorothiazide	DMUSZHD	Approved	Hydrochlorothiazide affects the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[40]
Saquinavir	DMG814N	Approved	Saquinavir affects the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[40]
Repaglinide	DM5SXUV	Approved	Repaglinide affects the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[40]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[33]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[41]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[42]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[33]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[44]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[45]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[46]

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 HLA class I histocompatibility antigen, alpha chain F (HLA-F).	[43]

References

• [1] Human HLAF adjacent transcript 10 promotes the formation of cancer initiating cells and cisplatin resistance in bladder cancer.Mol Med Rep. 2018 Jul;18(1):308-314. doi: 10.3892/mmr.2018.9005. Epub 2018 May 9.
• [2] Behet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity.Proc Natl Acad Sci U S A. 2014 Jun 17;111(24):8867-72. doi: 10.1073/pnas.1406575111. Epub 2014 May 12.
• [3] Bayesian and frequentist analysis of an Austrian genome-wide association study of colorectal cancer and advanced adenomas.Oncotarget. 2017 Oct 9;8(58):98623-98634. doi: 10.18632/oncotarget.21697. eCollection 2017 Nov 17.
• [4] Clinicopathological significance of human leukocyte antigen F-associated transcript 10 expression in colorectal cancer.World J Gastrointest Oncol. 2019 Jan 15;11(1):9-16. doi: 10.4251/wjgo.v11.i1.9.
• [5] Association analysis of exonic variants of the gene encoding the GABAB receptor and idiopathic generalized epilepsy.Am J Med Genet. 1999 Aug 20;88(4):305-10. doi: 10.1002/(sici)1096-8628(19990820)88:4<305::aid-ajmg5>3.0.co;2-x.
• [6] Alteration of HLA-F and HLA I antigen expression in the tumor is associated with survival in patients with esophageal squamous cell carcinoma.Int J Cancer. 2013 Jan 1;132(1):82-9. doi: 10.1002/ijc.27621. Epub 2012 May 17.
• [7] Human leukocyte antigen (HLA)-E and HLA-F expression in gastric cancer.Anticancer Res. 2015 Apr;35(4):2279-85.
• [8] Correlation of alteration of HLA-F expression and clinical characterization in 593 brain glioma samples.J Neuroinflammation. 2019 Feb 12;16(1):33. doi: 10.1186/s12974-019-1418-3.
• [9] Lesion HLA-F expression is irrelevant to prognosis for patients with gastric cancer.Hum Immunol. 2013 Jul;74(7):828-32. doi: 10.1016/j.humimm.2013.03.002. Epub 2013 Mar 27.
• [10] 46,XX, inv(6)(p21.1p23) in a pedigree with hereditary haemochromatosis.J Med Genet. 1997 Jan;34(1):24-7. doi: 10.1136/jmg.34.1.24.
• [11] Non-classical MHC- genes in chronic hepatitis B and hepatocellular carcinoma.Immunogenetics. 2012 Mar;64(3):251-8. doi: 10.1007/s00251-011-0580-2. Epub 2011 Oct 21.
• [12] Interactions Between KIR3DS1 and HLA-F Activate Natural Killer Cells to Control HCV Replication in Cell Culture.Gastroenterology. 2018 Nov;155(5):1366-1371.e3. doi: 10.1053/j.gastro.2018.07.019. Epub 2018 Jul 19.
• [13] Human Leukocyte Antigen F Locus Adjacent Transcript 10 Overexpression Disturbs WISP1 Protein and mRNA Expression to Promote Hepatocellular Carcinoma Progression.Hepatology. 2018 Dec;68(6):2268-2284. doi: 10.1002/hep.30105. Epub 2018 Nov 8.
• [14] HLA-F*01:01 presents peptides with N-terminal flexibility and a preferred length of 16 residues.Immunogenetics. 2019 May;71(5-6):353-360. doi: 10.1007/s00251-019-01112-1. Epub 2019 Apr 2.
• [15] Linkage analysis in familial melanoma kindreds to markers on chromosome 6p.Int J Cancer. 1994 Dec 15;59(6):771-5. doi: 10.1002/ijc.2910590611.
• [16] Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci.Nat Genet. 2009 Jul;41(7):776-82. doi: 10.1038/ng.401. Epub 2009 Jun 14.
• [17] Genome-wide association database developed in the Japanese Integrated Database Project.J Hum Genet. 2009 Sep;54(9):543-6. doi: 10.1038/jhg.2009.68. Epub 2009 Jul 24.
• [18] Promoter polymorphisms of the HLA-G gene, but not the HLA-E and HLA-F genes, is associated with non-segmental vitiligo patients in the Korean population.Arch Dermatol Res. 2011 Nov;303(9):679-84. doi: 10.1007/s00403-011-1160-x. Epub 2011 Aug 17.
• [19] The Emerging Roles of Human Leukocyte Antigen-F in Immune Modulation and Viral Infection.Front Immunol. 2019 May 10;10:964. doi: 10.3389/fimmu.2019.00964. eCollection 2019.
• [20] Mapping, genomic structure, and polymorphisms of the human GABABR1 receptor gene: evaluation of its involvement in idiopathic generalized epilepsy.Neurogenetics. 1998 Dec;2(1):47-54. doi: 10.1007/s100480050051.
• [21] Genome-wide association study reveals multiple nasopharyngeal carcinoma-associated loci within the HLA region at chromosome 6p21.3.Am J Hum Genet. 2009 Aug;85(2):194-203. doi: 10.1016/j.ajhg.2009.07.007. Epub 2009 Aug 6.
• [22] Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis.Nat Med. 2016 Apr;22(4):397-403. doi: 10.1038/nm.4052. Epub 2016 Feb 29.
• [23] Nonclassical human leukocyte antigen (HLA-G, HLA-E, and HLA-F) in coronary artery disease.Hum Immunol. 2016 Apr;77(4):325-9. doi: 10.1016/j.humimm.2016.01.008. Epub 2016 Jan 11.
• [24] Genetic associations of common deletion polymorphisms in families with Avellino corneal dystrophy.Biochem Biophys Res Commun. 2009 Oct 2;387(4):688-93. doi: 10.1016/j.bbrc.2009.07.084. Epub 2009 Jul 19.
• [25] Linkage analysis of 6p21 polymorphic markers and the hereditary hemochromatosis: localization of the gene centromeric to HLA-F.Hum Mol Genet. 1993 May;2(5):571-6. doi: 10.1093/hmg/2.5.571.
• [26] Genetic variation at the glycosaminoglycan metabolism pathway contributes to the risk of psoriatic arthritis but not psoriasis.Ann Rheum Dis. 2019 Mar;78(3):e214158. doi: 10.1136/annrheumdis-2018-214158. Epub 2018 Dec 14.
• [27] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [28] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [29] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [30] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [31] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [32] Changes in gene expression profiles of multiple myeloma cells induced by arsenic trioxide (ATO): possible mechanisms to explain ATO resistance in vivo. Br J Haematol. 2005 Mar;128(5):636-44.
• [33] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [34] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [35] 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.
• [36] [Mifepristone inhibits the progesterone-induced expressions of HLA-G, -E, -F genes in trophoblasts during first trimester]. Zhonghua Yi Xue Za Zhi. 2012 Jan 3;92(1):15-7.
• [37] 5-Fluorouracil up-regulates interferon pathway gene expression in esophageal cancer cells. Anticancer Res. 2005 Sep-Oct;25(5):3271-8.
• [38] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [39] Effect of nephrotoxicants and hepatotoxicants on gene expression profile in human peripheral blood mononuclear cells. Biochem Biophys Res Commun. 2010 Oct 15;401(2):245-50. doi: 10.1016/j.bbrc.2010.09.039. Epub 2010 Sep 16.
• [40] Systems pharmacological analysis of drugs inducing stevens-johnson syndrome and toxic epidermal necrolysis. Chem Res Toxicol. 2015 May 18;28(5):927-34. doi: 10.1021/tx5005248. Epub 2015 Apr 3.
• [41] Resveratrol inhibits pancreatic cancer cell proliferation through transcriptional induction of macrophage inhibitory cytokine-1. J Surg Res. 2007 Apr;138(2):163-9. doi: 10.1016/j.jss.2006.05.037. Epub 2007 Jan 25.
• [42] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [43] 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.
• [44] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [45] Linking site-specific loss of histone acetylation to repression of gene expression by the mycotoxin ochratoxin A. Arch Toxicol. 2018 Feb;92(2):995-1014.
• [46] Differential response of Mono Mac 6, BEAS-2B, and Jurkat cells to indoor dust. Environ Health Perspect. 2007 Sep;115(9):1325-32.