Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0UCK62)

• DOT Name: Host cell factor 1 (HCFC1)
• Synonyms: HCF; HCF-1; C1 factor; CFF; VCAF; VP16 accessory protein
• Gene Name: HCFC1
• Related Disease:
  Methylmalonic acidemia with homocystinuria, type cblX
  X-linked intellectual disability
  Central diabetes insipidus
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Cystic fibrosis
  Dystonia
  Herpes simplex infection
  Intellectual disability, X-linked 1
  Leukemia
  Liver cancer
  Metabolic disorder
  Neoplasm
  Non-alcoholic fatty liver disease
  Non-alcoholic steatohepatitis
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Systemic lupus erythematosus
  Carcinoma of liver and intrahepatic biliary tract
  Meniere disease
  Muscular dystrophy
  Nervous system disease
  Neurodevelopmental disorder
  Vitamin B12 deficiency
  Non-syndromic X-linked intellectual disability
  Cognitive impairment
  Keratoconjunctivitis sicca
  Neuroblastoma
• UniProt ID: HCFC1_HUMAN
• PDB ID: 4GO6; 4N39; 4N3A; 4N3B; 4N3C; 5LWV; 6MA1; 6MA2; 6MA3; 6MA4; 6MA5
• Pfam ID: PF01344 ; PF13415 ; PF13854
• Sequence:
  MASAVSPANLPAVLLQPRWKRVVGWSGPVPRPRHGHRAVAIKELIVVFGGGNEGIVDELH
  VYNTATNQWFIPAVRGDIPPGCAAYGFVCDGTRLLVFGGMVEYGKYSNDLYELQASRWEW
  KRLKAKTPKNGPPPCPRLGHSFSLVGNKCYLFGGLANDSEDPKNNIPRYLNDLYILELRP
  GSGVVAWDIPITYGVLPPPRESHTAVVYTEKDNKKSKLVIYGGMSGCRLGDLWTLDIDTL
  TWNKPSLSGVAPLPRSLHSATTIGNKMYVFGGWVPLVMDDVKVATHEKEWKCTNTLACLN
  LDTMAWETILMDTLEDNIPRARAGHCAVAINTRLYIWSGRDGYRKAWNNQVCCKDLWYLE
  TEKPPPPARVQLVRANTNSLEVSWGAVATADSYLLQLQKYDIPATAATATSPTPNPVPSV
  PANPPKSPAPAAAAPAVQPLTQVGITLLPQAAPAPPTTTTIQVLPTVPGSSISVPTAART
  QGVPAVLKVTGPQATTGTPLVTMRPASQAGKAPVTVTSLPAGVRMVVPTQSAQGTVIGSS
  PQMSGMAALAAAAAATQKIPPSSAPTVLSVPAGTTIVKTMAVTPGTTTLPATVKVASSPV
  MVSNPATRMLKTAAAQVGTSVSSATNTSTRPIITVHKSGTVTVAQQAQVVTTVVGGVTKT
  ITLVKSPISVPGGSALISNLGKVMSVVQTKPVQTSAVTGQASTGPVTQIIQTKGPLPAGT
  ILKLVTSADGKPTTIITTTQASGAGTKPTILGISSVSPSTTKPGTTTIIKTIPMSAIITQ
  AGATGVTSSPGIKSPITIITTKVMTSGTGAPAKIITAVPKIATGHGQQGVTQVVLKGAPG
  QPGTILRTVPMGGVRLVTPVTVSAVKPAVTTLVVKGTTGVTTLGTVTGTVSTSLAGAGGH
  STSASLATPITTLGTIATLSSQVINPTAITVSAAQTTLTAAGGLTTPTITMQPVSQPTQV
  TLITAPSGVEAQPVHDLPVSILASPTTEQPTATVTIADSGQGDVQPGTVTLVCSNPPCET
  HETGTTNTATTTVVANLGGHPQPTQVQFVCDRQEAAASLVTSTVGQQNGSVVRVCSNPPC
  ETHETGTTNTATTATSNMAGQHGCSNPPCETHETGTTNTATTAMSSVGANHQRDARRACA
  AGTPAVIRISVATGALEAAQGSKSQCQTRQTSATSTTMTVMATGAPCSAGPLLGPSMARE
  PGGRSPAFVQLAPLSSKVRLSSPSIKDLPAGRHSHAVSTAAMTRSSVGAGEPRMAPVCES
  LQGGSPSTTVTVTALEALLCPSATVTQVCSNPPCETHETGTTNTATTSNAGSAQRVCSNP
  PCETHETGTTHTATTATSNGGTGQPEGGQQPPAGRPCETHQTTSTGTTMSVSVGALLPDA
  TSSHRTVESGLEVAAAPSVTPQAGTALLAPFPTQRVCSNPPCETHETGTTHTATTVTSNM
  SSNQDPPPAASDQGEVESTQGDSVNITSSSAITTTVSSTLTRAVTTVTQSTPVPGPSVPP
  PEELQVSPGPRQQLPPRQLLQSASTALMGESAEVLSASQTPELPAAVDLSSTGEPSSGQE
  SAGSAVVATVVVQPPPPTQSEVDQLSLPQELMAEAQAGTTTLMVTGLTPEELAVTAAAEA
  AAQAAATEEAQALAIQAVLQAAQQAVMGTGEPMDTSEAAATVTQAELGHLSAEGQEGQAT
  TIPIVLTQQELAALVQQQQLQEAQAQQQHHHLPTEALAPADSLNDPAIESNCLNELAGTV
  PSTVALLPSTATESLAPSNTFVAPQPVVVASPAKLQAAATLTEVANGIESLGVKPDLPPP
  PSKAPMKKENQWFDVGVIKGTNVMVTHYFLPPDDAVPSDDDLGTVPDYNQLKKQELQPGT
  AYKFRVAGINACGRGPFSEISAFKTCLPGFPGAPCAIKISKSPDGAHLTWEPPSVTSGKI
  IEYSVYLAIQSSQAGGELKSSTPAQLAFMRVYCGPSPSCLVQSSSLSNAHIDYTTKPAII
  FRIAARNEKGYGPATQVRWLQETSKDSSGTKPANKRPMSSPEMKSAPKKSKADGQ
• Function: Transcriptional coregulator. Involved in control of the cell cycle. Also antagonizes transactivation by ZBTB17 and GABP2; represses ZBTB17 activation of the p15(INK4b) promoter and inhibits its ability to recruit p300. Coactivator for EGR2 and GABP2. Tethers the chromatin modifying Set1/Ash2 histone H3 'Lys-4' methyltransferase (H3K4me) and Sin3 histone deacetylase (HDAC) complexes (involved in the activation and repression of transcription, respectively) together. Component of a THAP1/THAP3-HCFC1-OGT complex that is required for the regulation of the transcriptional activity of RRM1. As part of the NSL complex it may be involved in acetylation of nucleosomal histone H4 on several lysine residues. Recruits KMT2E/MLL5 to E2F1 responsive promoters promoting transcriptional activation and thereby facilitates G1 to S phase transition. Modulates expression of homeobox protein PDX1, perhaps acting in concert with transcription factor E2F1, thereby regulating pancreatic beta-cell growth and glucose-stimulated insulin secretion. May negatively modulate transcriptional activity of FOXO3; (Microbial infection) In case of human herpes simplex virus (HSV) infection, HCFC1 forms a multiprotein-DNA complex with the viral transactivator protein VP16 and POU2F1 thereby enabling the transcription of the viral immediate early genes.
• Tissue Specificity: Highly expressed in fetal tissues and the adult kidney. Present in all tissues tested.
• KEGG Pathway:
  Polycomb repressive complex (hsa03083)
  Cobalamin transport and metabolism (hsa04980)
  Herpes simplex virus 1 infection (hsa05168)
• Reactome Pathway:
  HATs acetylate histones (R-HSA-3214847)
  UCH proteinases (R-HSA-5689603)
  Formation of WDR5-containing histone-modifying complexes (R-HSA-9772755)
  Transcriptional activation of mitochondrial biogenesis (R-HSA-2151201)

Molecular Interaction Atlas (MIA) of This DOT

31 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Methylmalonic acidemia with homocystinuria, type cblX	DISUMU47	Definitive	X-linked	[1]
X-linked intellectual disability	DISYJBY3	Definitive	X-linked	[2]
Central diabetes insipidus	DISJ4P9O	Strong	Biomarker	[3]
Cervical cancer	DISFSHPF	Strong	Biomarker	[4]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[6]
Dystonia	DISJLFGW	Strong	Genetic Variation	[7]
Herpes simplex infection	DISL1SAV	Strong	Biomarker	[8]
Intellectual disability, X-linked 1	DISET38E	Strong	GermlineCausalMutation	[9]
Leukemia	DISNAKFL	Strong	Altered Expression	[10]
Liver cancer	DISDE4BI	Strong	Biomarker	[11]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[14]
Non-alcoholic steatohepatitis	DIST4788	Strong	Biomarker	[14]
Prostate cancer	DISF190Y	Strong	Biomarker	[13]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[13]
Schizophrenia	DISSRV2N	Strong	Biomarker	[15]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[16]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	moderate	Genetic Variation	[11]
Meniere disease	DISC5R5F	moderate	Genetic Variation	[17]
Muscular dystrophy	DISJD6P7	moderate	Genetic Variation	[17]
Nervous system disease	DISJ7GGT	moderate	Biomarker	[18]
Neurodevelopmental disorder	DIS372XH	moderate	Biomarker	[18]
Vitamin B12 deficiency	DIS91UJ1	moderate	Altered Expression	[18]
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[9]
Cognitive impairment	DISH2ERD	Disputed	Genetic Variation	[19]
Keratoconjunctivitis sicca	DISNOENH	Limited	Biomarker	[20]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[21]

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 Host cell factor 1 (HCFC1).	[22]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Host cell factor 1 (HCFC1).	[27]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Host cell factor 1 (HCFC1).	[34]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Host cell factor 1 (HCFC1).	[35]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Host cell factor 1 (HCFC1).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Host cell factor 1 (HCFC1).	[23]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Host cell factor 1 (HCFC1).	[24]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Host cell factor 1 (HCFC1).	[25]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Host cell factor 1 (HCFC1).	[26]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Host cell factor 1 (HCFC1).	[28]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Host cell factor 1 (HCFC1).	[29]
Marinol	DM70IK5	Approved	Marinol increases the expression of Host cell factor 1 (HCFC1).	[30]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Host cell factor 1 (HCFC1).	[31]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Host cell factor 1 (HCFC1).	[32]
Vitamin C	DMXJ7O8	Approved	Vitamin C increases the expression of Host cell factor 1 (HCFC1).	[28]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Host cell factor 1 (HCFC1).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Host cell factor 1 (HCFC1).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Host cell factor 1 (HCFC1).	[37]
Rutin	DMEHRAJ	Investigative	Rutin increases the expression of Host cell factor 1 (HCFC1).	[38]
CATECHIN	DMY38SB	Investigative	CATECHIN increases the expression of Host cell factor 1 (HCFC1).	[38]

References

• [1] Localisation of the MRX3 gene for non-specific X linked mental retardation. J Med Genet. 1991 Jun;28(6):372-7. doi: 10.1136/jmg.28.6.372.
• [2] 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.
• [3] Effect of Clostridium difficile Prevalence in Hospitals and Nursing Homes on Risk of Infection.J Am Geriatr Soc. 2017 Jul;65(7):1527-1534. doi: 10.1111/jgs.14838. Epub 2017 Apr 10.
• [4] O-linked N-acetylglucosamine transferase promotes cervical cancer tumorigenesis through human papillomaviruses E6 and E7 oncogenes.Oncotarget. 2016 Jul 12;7(28):44596-44607. doi: 10.18632/oncotarget.10112.
• [5] A transcriptional regulatory role of the THAP11-HCF-1 complex in colon cancer cell function.Mol Cell Biol. 2012 May;32(9):1654-70. doi: 10.1128/MCB.06033-11. Epub 2012 Feb 27.
• [6] Overcoming barriers to a successful transition from pediatric to adult care.Pediatr Pulmonol. 2017 Nov;52(S48):S52-S60. doi: 10.1002/ppul.23778. Epub 2017 Sep 26.
• [7] Dystonia-causing mutations in the transcription factor THAP1 disrupt HCFC1 cofactor recruitment and alter gene expression.Hum Mol Genet. 2017 Aug 1;26(15):2975-2983. doi: 10.1093/hmg/ddx187.
• [8] Transcriptional Elongation of HSV Immediate Early Genes by the Super Elongation Complex Drives Lytic Infection and Reactivation from Latency.Cell Host Microbe. 2017 Apr 12;21(4):507-517.e5. doi: 10.1016/j.chom.2017.03.007.
• [9] A noncoding, regulatory mutation implicates HCFC1 in nonsyndromic intellectual disability. Am J Hum Genet. 2012 Oct 5;91(4):694-702. doi: 10.1016/j.ajhg.2012.08.011. Epub 2012 Sep 20.
• [10] E2F activation of S phase promoters via association with HCF-1 and the MLL family of histone H3K4 methyltransferases.Mol Cell. 2007 Jul 6;27(1):107-19. doi: 10.1016/j.molcel.2007.05.030.
• [11] Predominant modifier of extreme liver cancer susceptibility in C57BR/cdJ female mice localized to 6 Mb on chromosome 17.Carcinogenesis. 2009 May;30(5):879-85. doi: 10.1093/carcin/bgp054. Epub 2009 Mar 2.
• [12] Cortical and Commissural Defects Upon HCF-1 Loss in Nkx2.1-Derived Embryonic Neurons and Glia.Dev Neurobiol. 2019 Jun;79(6):578-595. doi: 10.1002/dneu.22704. Epub 2019 Jun 25.
• [13] Traditional Chinese Medicine CFF-1 induced cell growth inhibition, autophagy, and apoptosis via inhibiting EGFR-related pathways in prostate cancer.Cancer Med. 2018 Apr;7(4):1546-1559. doi: 10.1002/cam4.1419. Epub 2018 Mar 13.
• [14] Rapid Recapitulation of Nonalcoholic Steatohepatitis upon Loss of Host Cell Factor 1 Function in Mouse Hepatocytes.Mol Cell Biol. 2019 Feb 15;39(5):e00405-18. doi: 10.1128/MCB.00405-18.
• [15] Simplifying the human serum proteome for discriminating patients with bipolar disorder of other psychiatry conditions.Clin Biochem. 2017 Dec;50(18):1118-1125. doi: 10.1016/j.clinbiochem.2017.06.009. Epub 2017 Jun 27.
• [16] Fine mapping of Xq28: both MECP2 and IRAK1 contribute to risk for systemic lupus erythematosus in multiple ancestral groups.Ann Rheum Dis. 2013 Mar;72(3):437-44. doi: 10.1136/annrheumdis-2012-201851. Epub 2012 Aug 17.
• [17] Sequence variants in host cell factor C1 are associated with Mnire's disease.Otol Neurotol. 2008 Jun;29(4):561-6. doi: 10.1097/MAO.0b013e318168d23b.
• [18] HCFC1 loss-of-function mutations disrupt neuronal and neural progenitor cells of the developing brain.Hum Mol Genet. 2015 Jun 15;24(12):3335-47. doi: 10.1093/hmg/ddv083. Epub 2015 Mar 3.
• [19] Efficient strategy for the molecular diagnosis of intellectual disability using targeted high-throughput sequencing.J Med Genet. 2014 Nov;51(11):724-36. doi: 10.1136/jmedgenet-2014-102554. Epub 2014 Aug 28.
• [20] Relation of accommodative microfluctuation with dry eye symptoms in short tear break-up time dry eye.PLoS One. 2017 Sep 8;12(9):e0184296. doi: 10.1371/journal.pone.0184296. eCollection 2017.
• [21] The Cellular Coactivator HCF-1 Is Required for Glucocorticoid Receptor-Mediated Transcription of Bovine Herpesvirus 1 Immediate Early Genes.J Virol. 2018 Aug 16;92(17):e00987-18. doi: 10.1128/JVI.00987-18. Print 2018 Sep 1.
• [22] 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.
• [23] 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.
• [24] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [25] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [26] 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.
• [27] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [28] Synergistic effects of arsenic trioxide combined with ascorbic acid in human osteosarcoma MG-63 cells: a systems biology analysis. Eur Rev Med Pharmacol Sci. 2014;18(24):3877-88.
• [29] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [30] 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.
• [31] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [32] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [33] 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.
• [34] 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.
• [35] 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.
• [36] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [37] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [38] Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells. J Nutr. 2004 Oct;134(10):2509-16.