Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7AKCFQ)

• DOT Name: Huntingtin-interacting protein 1 (HIP1)
• Synonyms: HIP-1; Huntingtin-interacting protein I; HIP-I
• Gene Name: HIP1
• Related Disease:
  Arthritis
  Acute monocytic leukemia
  Acute myelogenous leukaemia
  Advanced cancer
  Alzheimer disease
  B-cell neoplasm
  Breast neoplasm
  Chronic myelomonocytic leukemia
  Classic Hodgkin lymphoma
  Colon cancer
  Colon carcinoma
  Colonic neoplasm
  Epilepsy
  Epithelial neoplasm
  Haematological malignancy
  Hepatocellular carcinoma
  Huntington disease
  Hutchinson-Gilford progeria syndrome
  leukaemia
  Leukemia
  Lung adenocarcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Prostate cancer
  Prostate neoplasm
  Tuberculosis
  Brachydactyly type A1
  Breast cancer
  Breast carcinoma
  Chronic myelomonocytic leukaemia
  Nervous system disease
  Non-small-cell lung cancer
  Prostate carcinoma
  Rheumatoid arthritis
  Systemic lupus erythematosus
• UniProt ID: HIP1_HUMAN
• PDB ID: 2NO2; 2QA7; 3I00
• Pfam ID: PF07651 ; PF16515 ; PF01608
• Sequence:
  MDRMASSMKQVPNPLPKVLSRRGVGAGLEAAERESFERTQTVSINKAINTQEVAVKEKHA
  RTCILGTHHEKGAQTFWSVVNRLPLSSNAVLCWKFCHVFHKLLRDGHPNVLKDSLRYRNE
  LSDMSRMWGHLSEGYGQLCSIYLKLLRTKMEYHTKNPRFPGNLQMSDRQLDEAGESDVNN
  FFQLTVEMFDYLECELNLFQTVFNSLDMSRSVSVTAAGQCRLAPLIQVILDCSHLYDYTV
  KLLFKLHSCLPADTLQGHRDRFMEQFTKLKDLFYRSSNLQYFKRLIQIPQLPENPPNFLR
  ASALSEHISPVVVIPAEASSPDSEPVLEKDDLMDMDASQQNLFDNKFDDIFGSSFSSDPF
  NFNSQNGVNKDEKDHLIERLYREISGLKAQLENMKTESQRVVLQLKGHVSELEADLAEQQ
  HLRQQAADDCEFLRAELDELRRQREDTEKAQRSLSEIERKAQANEQRYSKLKEKYSELVQ
  NHADLLRKNAEVTKQVSMARQAQVDLEREKKELEDSLERISDQGQRKTQEQLEVLESLKQ
  ELATSQRELQVLQGSLETSAQSEANWAAEFAELEKERDSLVSGAAHREEELSALRKELQD
  TQLKLASTEESMCQLAKDQRKMLLVGSRKAAEQVIQDALNQLEEPPLISCAGSADHLLST
  VTSISSCIEQLEKSWSQYLACPEDISGLLHSITLLAHLTSDAIAHGATTCLRAPPEPADS
  LTEACKQYGRETLAYLASLEEEGSLENADSTAMRNCLSKIKAIGEELLPRGLDIKQEELG
  DLVDKEMAATSAAIETATARIEEMLSKSRAGDTGVKLEVNERILGCCTSLMQAIQVLIVA
  SKDLQREIVESGRGTASPKEFYAKNSRWTEGLISASKAVGWGATVMVDAADLVVQGRGKF
  EELMVCSHEIAASTAQLVAASKVKADKDSPNLAQLQQASRGVNQATAGVVASTISGKSQI
  EETDNMDFSSMTLTQIKRQEMDSQVRVLELENELQKERQKLGELRKKHYELAGVAEGWEE
  GTEASPPTLQEVVTEKE
• Function: Plays a role in clathrin-mediated endocytosis and trafficking. Involved in regulating AMPA receptor trafficking in the central nervous system in an NMDA-dependent manner. Regulates presynaptic nerve terminal activity. Enhances androgen receptor (AR)-mediated transcription. May act as a proapoptotic protein that induces cell death by acting through the intrinsic apoptosis pathway. Binds 3-phosphoinositides (via ENTH domain). May act through the ENTH domain to promote cell survival by stabilizing receptor tyrosine kinases following ligand-induced endocytosis. May play a functional role in the cell filament networks. May be required for differentiation, proliferation, and/or survival of somatic and germline progenitors.
• Tissue Specificity: Ubiquitously expressed with the highest level in brain. Expression is up-regulated in prostate and colon cancer.
• KEGG Pathway:
  Huntington disease (hsa05016)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
• Reactome Pathway:
  ALK mutants bind TKIs (R-HSA-9700645)
  Signaling by ALK fusions and activated point mutants (R-HSA-9725370)
  Clathrin-mediated endocytosis (R-HSA-8856828)

Molecular Interaction Atlas (MIA) of This DOT

35 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arthritis	DIST1YEL	Definitive	Genetic Variation	[1]
Acute monocytic leukemia	DIS28NEL	Strong	Altered Expression	[2]
Acute myelogenous leukaemia	DISCSPTN	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Alzheimer disease	DISF8S70	Strong	Biomarker	[3]
B-cell neoplasm	DISVY326	Strong	Biomarker	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Chronic myelomonocytic leukemia	DISIL8UR	Strong	Biomarker	[6]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[7]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[7]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[7]
Epilepsy	DISBB28L	Strong	Genetic Variation	[8]
Epithelial neoplasm	DIS0T594	Strong	Altered Expression	[5]
Haematological malignancy	DISCDP7W	Strong	Biomarker	[9]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[10]
Huntington disease	DISQPLA4	Strong	Biomarker	[11]
Hutchinson-Gilford progeria syndrome	DISY55BU	Strong	Altered Expression	[12]
leukaemia	DISS7D1V	Strong	Altered Expression	[2]
Leukemia	DISNAKFL	Strong	Altered Expression	[2]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[13]
Metastatic malignant neoplasm	DIS86UK6	Strong	Biomarker	[13]
Neoplasm	DISZKGEW	Strong	Biomarker	[14]
Prostate cancer	DISF190Y	Strong	Altered Expression	[15]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[16]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[17]
Brachydactyly type A1	DISZUO15	Limited	Genetic Variation	[18]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[19]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[19]
Chronic myelomonocytic leukaemia	DISDN5P7	Limited	Biomarker	[20]
Nervous system disease	DISJ7GGT	Limited	Genetic Variation	[21]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Altered Expression	[13]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[22]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[23]
Systemic lupus erythematosus	DISI1SZ7	Limited	Genetic Variation	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Huntingtin-interacting protein 1 (HIP1).	[25]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Huntingtin-interacting protein 1 (HIP1).	[26]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Huntingtin-interacting protein 1 (HIP1).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Huntingtin-interacting protein 1 (HIP1).	[28]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Huntingtin-interacting protein 1 (HIP1).	[29]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Huntingtin-interacting protein 1 (HIP1).	[31]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Huntingtin-interacting protein 1 (HIP1).	[32]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Huntingtin-interacting protein 1 (HIP1).	[33]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Huntingtin-interacting protein 1 (HIP1).	[34]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Huntingtin-interacting protein 1 (HIP1).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Huntingtin-interacting protein 1 (HIP1).	[36]
Scriptaid	DM9JZ21	Preclinical	Scriptaid increases the expression of Huntingtin-interacting protein 1 (HIP1).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Huntingtin-interacting protein 1 (HIP1).	[39]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID increases the expression of Huntingtin-interacting protein 1 (HIP1).	[40]
Apicidin	DM83WVF	Investigative	Apicidin increases the expression of Huntingtin-interacting protein 1 (HIP1).	[31]
DZNep	DM0JXBK	Investigative	DZNep decreases the expression of Huntingtin-interacting protein 1 (HIP1).	[31]

3 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Huntingtin-interacting protein 1 (HIP1).	[30]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Huntingtin-interacting protein 1 (HIP1).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Huntingtin-interacting protein 1 (HIP1).	[38]

References

• [1] Huntingtin-interacting protein 1 (HIP1) regulates arthritis severity and synovial fibroblast invasiveness by altering PDGFR and Rac1 signalling.Ann Rheum Dis. 2018 Nov;77(11):1627-1635. doi: 10.1136/annrheumdis-2018-213498. Epub 2018 Jul 26.
• [2] Prognostic significance of huntingtin interacting protein 1 expression on patients with acute myeloid leukemia.Sci Rep. 2017 Apr 28;7:45960. doi: 10.1038/srep45960.
• [3] A genome-wide association study of aging.Neurobiol Aging. 2011 Nov;32(11):2109.e15-28. doi: 10.1016/j.neurobiolaging.2011.05.026. Epub 2011 Jul 22.
• [4] Aberrant Huntingtin interacting protein 1 in lymphoid malignancies.Cancer Res. 2007 Sep 15;67(18):8923-31. doi: 10.1158/0008-5472.CAN-07-2153.
• [5] Altered receptor trafficking in Huntingtin Interacting Protein 1-transformed cells.Cancer Cell. 2003 May;3(5):471-82. doi: 10.1016/s1535-6108(03)00107-7.
• [6] Sensitivity to imatinib but low frequency of the TEL/PDGFRbeta fusion protein in chronic myelomonocytic leukemia.Haematologica. 2003 Apr;88(4):408-15.
• [7] Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival.J Clin Invest. 2002 Aug;110(3):351-60. doi: 10.1172/JCI15529.
• [8] Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits.Eur J Hum Genet. 2014 Jan;22(1):64-70. doi: 10.1038/ejhg.2013.101. Epub 2013 Jun 12.
• [9] Fusion of Huntingtin interacting protein 1 to platelet-derived growth factor beta receptor (PDGFbetaR) in chronic myelomonocytic leukemia with t(5;7)(q33;q11.2).Blood. 1998 Jun 15;91(12):4419-26.
• [10] Hedgehog signaling in human hepatocellular carcinoma.Cancer Biol Ther. 2006 Jan;5(1):111-7. doi: 10.4161/cbt.5.1.2379. Epub 2006 Jan 5.
• [11] Replacement of charged and polar residues in the coiled-coiled interface of huntingtin-interacting protein 1 (HIP1) causes aggregation and cell death.FEBS Lett. 2012 Sep 21;586(19):3030-6. doi: 10.1016/j.febslet.2012.07.011. Epub 2012 Jul 23.
• [12] Increased expression of the Huntingtin interacting protein-1 gene in cells from Hutchinson Gilford Syndrome (Progeria) patients and aged donors.J Gerontol A Biol Sci Med Sci. 2003 Oct;58(10):B873-8. doi: 10.1093/gerona/58.10.b873.
• [13] Huntingtin-Interacting Protein-1 Is an Early-Stage Prognostic Biomarker of Lung Adenocarcinoma and Suppresses Metastasis via Akt-mediated Epithelial-Mesenchymal Transition.Am J Respir Crit Care Med. 2016 Apr 15;193(8):869-80. doi: 10.1164/rccm.201412-2226OC.
• [14] Knockdown of HIP1 expression promotes ligandinduced endocytosis of EGFR in HeLa cells.Oncol Rep. 2017 Dec;38(6):3387-3391. doi: 10.3892/or.2017.6025. Epub 2017 Oct 12.
• [15] Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression.Neoplasia. 2008 Aug;10(8):847-56. doi: 10.1593/neo.08450.
• [16] Use of a cryptic splice site for the expression of huntingtin interacting protein 1 in select normal and neoplastic tissues.Cancer Res. 2008 Feb 15;68(4):1064-73. doi: 10.1158/0008-5472.CAN-07-5892.
• [17] Structure Determination of Mycobacterium tuberculosis Serine Protease Hip1 (Rv2224c).Biochemistry. 2017 May 2;56(17):2304-2314. doi: 10.1021/acs.biochem.6b01066. Epub 2017 Apr 7.
• [18] A mutation in Ihh that causes digit abnormalities alters its signalling capacity and range.Nature. 2009 Apr 30;458(7242):1196-200. doi: 10.1038/nature07862. Epub 2009 Mar 1.
• [19] SHON expression predicts response and relapse risk of breast cancer patients after anthracycline-based combination chemotherapy or tamoxifen treatment.Br J Cancer. 2019 Apr;120(7):728-745. doi: 10.1038/s41416-019-0405-x. Epub 2019 Feb 28.
• [20] Huntingtin interacting protein 1 Is a clathrin coat binding protein required for differentiation of late spermatogenic progenitors.Mol Cell Biol. 2001 Nov;21(22):7796-806. doi: 10.1128/MCB.21.22.7796-7806.2001.
• [21] Recurrent distal 7q11.23 deletion including HIP1 and YWHAG identified in patients with intellectual disabilities, epilepsy, and neurobehavioral problems.Am J Hum Genet. 2010 Dec 10;87(6):857-65. doi: 10.1016/j.ajhg.2010.10.019. Epub 2010 Nov 25.
• [22] Serum antibodies to huntingtin interacting protein-1: a new blood test for prostate cancer.Cancer Res. 2005 May 15;65(10):4126-33. doi: 10.1158/0008-5472.CAN-04-4658.
• [23] Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes.Nat Commun. 2018 May 15;9(1):1921. doi: 10.1038/s41467-018-04310-9.
• [24] Identification of a Systemic Lupus Erythematosus Risk Locus Spanning ATG16L2, FCHSD2, and P2RY2 in Koreans.Arthritis Rheumatol. 2016 May;68(5):1197-1209. doi: 10.1002/art.39548.
• [25] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [26] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [27] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [28] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [29] 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.
• [30] 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.
• [31] Development and validation of the TGx-HDACi transcriptomic biomarker to detect histone deacetylase inhibitors in human TK6 cells. Arch Toxicol. 2021 May;95(5):1631-1645. doi: 10.1007/s00204-021-03014-2. Epub 2021 Mar 26.
• [32] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [33] 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.
• [34] Gene expression signatures after ethanol exposure in differentiating embryoid bodies. Toxicol In Vitro. 2018 Feb;46:66-76.
• [35] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [36] 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.
• [37] 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.
• [38] 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.
• [39] 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.
• [40] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.