Details of Drug Off-Target (DOT)

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

• DOT Name: Hypoxia up-regulated protein 1 (HYOU1)
• Synonyms: 150 kDa oxygen-regulated protein; ORP-150; 170 kDa glucose-regulated protein; GRP-170
• Gene Name: HYOU1
• Related Disease:
  Spinocerebellar ataxia type 17
  Adult glioblastoma
  Advanced cancer
  Alzheimer disease
  Breast cancer
  Breast carcinoma
  Epithelial ovarian cancer
  Fatty liver disease
  Glioblastoma multiforme
  Neoplasm
  Obesity
  Prostate cancer
  Prostate carcinoma
  Type-1/2 diabetes
  X-linked reticulate pigmentary disorder
  Diabetic kidney disease
  Proliferative diabetic retinopathy
  Colorectal carcinoma
  Granulocytopenia with immunoglobulin abnormality
• UniProt ID: HYOU1_HUMAN
• Pfam ID: PF00012
• Sequence:
  MADKVRRQRPRRRVCWALVAVLLADLLALSDTLAVMSVDLGSESMKVAIVKPGVPMEIVL
  NKESRRKTPVIVTLKENERFFGDSAASMAIKNPKATLRYFQHLLGKQADNPHVALYQARF
  PEHELTFDPQRQTVHFQISSQLQFSPEEVLGMVLNYSRSLAEDFAEQPIKDAVITVPVFF
  NQAERRAVLQAARMAGLKVLQLINDNTATALSYGVFRRKDINTTAQNIMFYDMGSGSTVC
  TIVTYQMVKTKEAGMQPQLQIRGVGFDRTLGGLEMELRLRERLAGLFNEQRKGQRAKDVR
  ENPRAMAKLLREANRLKTVLSANADHMAQIEGLMDDVDFKAKVTRVEFEELCADLFERVP
  GPVQQALQSAEMSLDEIEQVILVGGATRVPRVQEVLLKAVGKEELGKNINADEAAAMGAV
  YQAAALSKAFKVKPFVVRDAVVYPILVEFTREVEEEPGIHSLKHNKRVLFSRMGPYPQRK
  VITFNRYSHDFNFHINYGDLGFLGPEDLRVFGSQNLTTVKLKGVGDSFKKYPDYESKGIK
  AHFNLDESGVLSLDRVESVFETLVEDSAEEESTLTKLGNTISSLFGGGTTPDAKENGTDT
  VQEEEESPAEGSKDEPGEQVELKEEAEAPVEDGSQPPPPEPKGDATPEGEKATEKENGDK
  SEAQKPSEKAEAGPEGVAPAPEGEKKQKPARKRRMVEEIGVELVVLDLPDLPEDKLAQSV
  QKLQDLTLRDLEKQEREKAANSLEAFIFETQDKLYQPEYQEVSTEEQREEISGKLSAAST
  WLEDEGVGATTVMLKEKLAELRKLCQGLFFRVEERKKWPERLSALDNLLNHSSMFLKGAR
  LIPEMDQIFTEVEMTTLEKVINETWAWKNATLAEQAKLPATEKPVLLSKDIEAKMMALDR
  EVQYLLNKAKFTKPRPRPKDKNGTRAEPPLNASASDQGEKVIPPAGQTEDAEPISEPEKV
  ETGSEPGDTEPLELGGPGAEPEQKEQSTGQKRPLKNDEL
• Function: Has a pivotal role in cytoprotective cellular mechanisms triggered by oxygen deprivation. May play a role as a molecular chaperone and participate in protein folding.
• Tissue Specificity: Highly expressed in tissues that contain well-developed endoplasmic reticulum and synthesize large amounts of secretory proteins. Highly expressed in liver and pancreas and lower expression in brain and kidney. Also expressed in macrophages within aortic atherosclerotic plaques, and in breast cancers.
• KEGG Pathway: Protein processing in endoplasmic reticulum (hsa04141)
• Reactome Pathway:
  XBP1(S) activates chaperone genes (R-HSA-381038)
  Scavenging by Class F Receptors (R-HSA-3000484)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Spinocerebellar ataxia type 17	DISJXO7P	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[3]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[5]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Obesity	DIS47Y1K	Strong	Biomarker	[6]
Prostate cancer	DISF190Y	Strong	Biomarker	[7]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[7]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[8]
X-linked reticulate pigmentary disorder	DIS0RB5A	Strong	Altered Expression	[8]
Diabetic kidney disease	DISJMWEY	moderate	Altered Expression	[9]
Proliferative diabetic retinopathy	DISQZ13G	moderate	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[10]
Granulocytopenia with immunoglobulin abnormality	DISXTLCK	Limited	Unknown	[11]

17 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 Hypoxia up-regulated protein 1 (HYOU1).	[12]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[14]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[18]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[19]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[20]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[21]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[22]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[23]
NVP-AUY922	DMTYXQF	Phase 2	NVP-AUY922 decreases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[26]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[27]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[29]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Hypoxia up-regulated protein 1 (HYOU1).	[30]

2 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 affects the methylation of Hypoxia up-regulated protein 1 (HYOU1).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Hypoxia up-regulated protein 1 (HYOU1).	[28]

References

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• [2] Regulation of tumor angiogenesis by oxygen-regulated protein 150, an inducible endoplasmic reticulum chaperone.Cancer Res. 2001 May 15;61(10):4206-13.
• [3] HYOU1 promotes cell growth and metastasis via activating PI3K/AKT signaling in epithelial ovarian cancer and predicts poor prognosis.Eur Rev Med Pharmacol Sci. 2019 Jan;23(10):4126-4135. doi: 10.26355/eurrev_201901_17914.
• [4] ORP150-CHIP chaperone antagonism control BACE1-mediated amyloid processing.J Cell Biochem. 2018 Jun;119(6):4615-4626. doi: 10.1002/jcb.26630. Epub 2018 Feb 27.
• [5] Protectin DX Ameliorates Hepatic Steatosis by Suppression of Endoplasmic Reticulum Stress via AMPK-Induced ORP150 Expression.J Pharmacol Exp Ther. 2018 Jun;365(3):485-493. doi: 10.1124/jpet.117.246686. Epub 2018 Mar 23.
• [6] Polymorphisms in the oxygen-regulated protein 150 gene (ORP150) are associated with insulin resistance in Pima Indians.Diabetes. 2002 May;51(5):1618-21. doi: 10.2337/diabetes.51.5.1618.
• [7] Antitumor effect of reduction of 150-kDa oxygen-regulated protein expression on human prostate cancer cells.Int J Urol. 2002 Oct;9(10):577-85. doi: 10.1046/j.1442-2042.2002.00519.x.
• [8] Association of 150-kDa oxygen-regulated protein with vascular endothelial growth factor in proliferative diabetic retinopathy.Acta Ophthalmol. 2018 Jun;96(4):e460-e467. doi: 10.1111/aos.13600. Epub 2017 Nov 2.
• [9] The 150-kDa oxygen-regulated protein (ORP150) regulates proteinuria in diabetic nephropathy via mediating VEGF.Exp Mol Pathol. 2019 Oct;110:104255. doi: 10.1016/j.yexmp.2019.04.014. Epub 2019 Apr 25.
• [10] Significant overexpression of Hsp110 gene during colorectal cancer progression.Oncol Rep. 2009 May;21(5):1235-41. doi: 10.3892/or_00000346.
• [11] Combined immunodeficiency and hypoglycemia associated with mutations in hypoxia upregulated 1. J Allergy Clin Immunol. 2017 Apr;139(4):1391-1393.e11. doi: 10.1016/j.jaci.2016.09.050. Epub 2016 Nov 29.
• [12] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [13] Inter-laboratory comparison of human renal proximal tubule (HK-2) transcriptome alterations due to Cyclosporine A exposure and medium exhaustion. Toxicol In Vitro. 2009 Apr;23(3):486-99.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [20] Microarray analysis of bicalutamide action on telomerase activity, p53 pathway and viability of prostate carcinoma cell lines. J Pharm Pharmacol. 2005 Jan;57(1):83-92.
• [21] Proteomic profile of aminoglutethimide-induced apoptosis in HL-60 cells: role of myeloperoxidase and arylamine free radicals. Chem Biol Interact. 2015 Sep 5;239:129-38.
• [22] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [23] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [24] Impact of Heat Shock Protein 90 Inhibition on the Proteomic Profile of Lung Adenocarcinoma as Measured by Two-Dimensional Electrophoresis Coupled with Mass Spectrometry. Cells. 2019 Jul 31;8(8):806. doi: 10.3390/cells8080806.
• [25] 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.
• [26] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [27] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [28] 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.
• [29] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [30] Evaluation of an in vitro model of androgen ablation and identification of the androgen responsive proteome in LNCaP cells. Proteomics. 2007 Jan;7(1):47-63.