Details of Drug Off-Target (DOT)

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

• DOT Name: Hypoxia-inducible factor 3-alpha (HIF3A)
• Synonyms: HIF-3-alpha; HIF3-alpha; Basic-helix-loop-helix-PAS protein MOP7; Class E basic helix-loop-helix protein 17; bHLHe17; HIF3-alpha-1; Inhibitory PAS domain protein; IPAS; Member of PAS protein 7; PAS domain-containing protein 7
• Gene Name: HIF3A
• Related Disease:
  Clear cell renal carcinoma
  Congenital contractural arachnodactyly
  Eclampsia
  Epithelial ovarian cancer
  Hepatocellular carcinoma
  Non-small-cell lung cancer
  Osteoarthritis
  Ovarian cancer
  Ovarian neoplasm
  Pulmonary hypertension
  Renal cell carcinoma
  Severe combined immunodeficiency
  Sheldon-hall syndrome
  Pancreatic cancer
  Recessive X-linked ichthyosis
  Parkinson disease
  Familial spontaneous pneumothorax
  Myasthenia gravis
  Obesity
• UniProt ID: HIF3A_HUMAN
• PDB ID: 4WN5
• Pfam ID: PF11413 ; PF00989 ; PF14598
• Sequence:
  MALGLQRARSTTELRKEKSRDAARSRRSQETEVLYQLAHTLPFARGVSAHLDKASIMRLT
  ISYLRMHRLCAAGEWNQVGAGGEPLDACYLKALEGFVMVLTAEGDMAYLSENVSKHLGLS
  QLELIGHSIFDFIHPCDQEELQDALTPQQTLSRRKVEAPTERCFSLRMKSTLTSRGRTLN
  LKAATWKVLNCSGHMRAYKPPAQTSPAGSPDSEPPLQCLVLICEAIPHPGSLEPPLGRGA
  FLSRHSLDMKFTYCDDRIAEVAGYSPDDLIGCSAYEYIHALDSDAVSKSIHTLLSKGQAV
  TGQYRFLARSGGYLWTQTQATVVSGGRGPQSESIVCVHFLISQVEETGVVLSLEQTEQHS
  RRPIQRGAPSQKDTPNPGDSLDTPGPRILAFLHPPSLSEAALAADPRRFCSPDLRRLLGP
  ILDGASVAATPSTPLATRHPQSPLSADLPDELPVGTENVHRLFTSGKDTEAVETDLDIAQ
  DADALDLEMLAPYISMDDDFQLNASEQLPRAYHRPLGAVPRPRARSFHGLSPPALEPSLL
  PRWGSDPRLSCSSPSRGDPSASSPMAGARKRTLAQSSEDEDEGVELLGVRPPKRSPSPEH
  ENFLLFPLSLSFLLTGGPAPGSLQDPSTPLLNLNEPLGLGPSLLSPYSDEDTTQPGGPFQ
  PRAGSAQAD
• Function: Acts as a transcriptional regulator in adaptive response to low oxygen tension. Acts as a regulator of hypoxia-inducible gene expression. Functions as an inhibitor of angiogenesis in hypoxic cells of the cornea. Plays a role in the development of the cardiorespiratory system. May also be involved in apoptosis; [Isoform 2]: Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. Also inhibits hypoxia-inducible ARNT-mediated gene expression; [Isoform 3]: Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation; [Isoform 4]: Attenuates the ability of transcription factor HIF1A and EPAS1/HIF2A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation. May act as a tumor suppressor and inhibits malignant cell transformation ; [Isoform 5]: Attenuates the ability of transcription factor HIF1A to bind to hypoxia-responsive elements (HRE) located within the enhancer/promoter of hypoxia-inducible target genes and hence inhibits HRE-driven transcriptional activation.
• Tissue Specificity: Expressed in vascular cells (at protein level) . Expressed in kidney . Expressed in lung epithelial cells . Expressed in endothelial cells (venous and arterial cells from umbilical cord and aortic endothelial cells) and in vascular smooth muscle cells (aorta) . Strongly expressed in the heart, placenta, and skeletal muscle, whereas a weak expression profile was found in the lung, liver, and kidney . Expressed weakly in cell renal cell carcinoma (CC-RCC) compared to normal renal cells . Expression is down-regulated in numerous kidney tumor cells compared to non tumor kidney tissues . Isoform 2 is expressed in heart, placenta, lung, liver, skeletal muscle and pancreas and in numerous cancer cell lines . Isoform 3 and isoform 4 are weakly expressed in heart, placenta, lung, liver, skeletal muscle and pancreas . Isoform 4 is expressed in fetal tissues, such as heart, brain, thymus, lung, liver, skeletal kidney and spleen . Isoform 3 is weakly expressed in fetal tissues, such as liver and kidney .
• Reactome Pathway:
  Transcriptional regulation of pluripotent stem cells (R-HSA-452723)
  Neddylation (R-HSA-8951664)
  Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[1]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Biomarker	[2]
Eclampsia	DISWPO8U	Strong	Posttranslational Modification	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[7]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[4]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[4]
Pulmonary hypertension	DIS1RSP5	Strong	Biomarker	[8]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[1]
Severe combined immunodeficiency	DIS6MF4Q	Strong	Altered Expression	[1]
Sheldon-hall syndrome	DISOCVMC	Strong	Altered Expression	[9]
Pancreatic cancer	DISJC981	moderate	Biomarker	[10]
Recessive X-linked ichthyosis	DISZY56W	moderate	Altered Expression	[11]
Parkinson disease	DISQVHKL	Disputed	Altered Expression	[12]
Familial spontaneous pneumothorax	DISNM7SU	Limited	Altered Expression	[13]
Myasthenia gravis	DISELRCI	Limited	Altered Expression	[14]
Obesity	DIS47Y1K	Limited	Biomarker	[15]

2 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 Hypoxia-inducible factor 3-alpha (HIF3A).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Hypoxia-inducible factor 3-alpha (HIF3A).	[23]

9 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 Hypoxia-inducible factor 3-alpha (HIF3A).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Hypoxia-inducible factor 3-alpha (HIF3A).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Hypoxia-inducible factor 3-alpha (HIF3A).	[19]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Hypoxia-inducible factor 3-alpha (HIF3A).	[20]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Hypoxia-inducible factor 3-alpha (HIF3A).	[21]
Isoproterenol	DMK7MEY	Approved	Isoproterenol increases the expression of Hypoxia-inducible factor 3-alpha (HIF3A).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Hypoxia-inducible factor 3-alpha (HIF3A).	[24]
Clioquinol	DM746BZ	Withdrawn from market	Clioquinol decreases the expression of Hypoxia-inducible factor 3-alpha (HIF3A).	[25]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Hypoxia-inducible factor 3-alpha (HIF3A).	[26]

References

• [1] Dominant-negative HIF-3 alpha 4 suppresses VHL-null renal cell carcinoma progression.Cell Cycle. 2007 Nov 15;6(22):2810-6. doi: 10.4161/cc.6.22.4947. Epub 2007 Aug 29.
• [2] Potential role of HIF-1-responsive microRNA210/HIF3 axis on gemcitabine resistance in cholangiocarcinoma cells.PLoS One. 2018 Jun 28;13(6):e0199827. doi: 10.1371/journal.pone.0199827. eCollection 2018.
• [3] Early-life determinants of hypoxia-inducible factor 3A gene(HIF3A) methylation: a birth cohort study.Clin Epigenetics. 2019 Jul 1;11(1):96. doi: 10.1186/s13148-019-0687-0.
• [4] LINC01342 promotes the progression of ovarian cancer by absorbing microRNA-30c-2-3p to upregulate HIF3A.J Cell Physiol. 2020 Apr;235(4):3939-3949. doi: 10.1002/jcp.29289. Epub 2019 Oct 9.
• [5] Tumour necrosis factor- suppresses the hypoxic response by NF-B-dependent induction of inhibitory PAS domain protein in PC12 cells.J Biochem. 2011 Sep;150(3):311-8. doi: 10.1093/jb/mvr061. Epub 2011 May 10.
• [6] MicroRNA-300 targets hypoxia inducible factor-3 alpha to inhibit tumorigenesis of human non-small cell lung cancer.Neoplasma. 2017;64(4):554-562. doi: 10.4149/neo_2017_409.
• [7] Overexpression of microRNA-210 promotes chondrocyte proliferation and extracellular matrix deposition by targeting HIF-3 in osteoarthritis.Mol Med Rep. 2016 Mar;13(3):2769-76. doi: 10.3892/mmr.2016.4878. Epub 2016 Feb 5.
• [8] Differential expression of three hypoxia-inducible factor-alpha subunits in pulmonary arteries of rat with hypoxia-induced hypertension.Acta Biochim Biophys Sin (Shanghai). 2005 Oct;37(10):665-72. doi: 10.1111/j.1745-7270.2005.00095.x.
• [9] A gain-of-function mutation in Tnni2 impeded bone development through increasing Hif3a expression in DA2B mice.PLoS Genet. 2014 Oct 23;10(10):e1004589. doi: 10.1371/journal.pgen.1004589. eCollection 2014 Oct.
• [10] HIF-3 Promotes Metastatic Phenotypes in Pancreatic Cancer by Transcriptional Regulation of the RhoC-ROCK1 Signaling Pathway.Mol Cancer Res. 2018 Jan;16(1):124-134. doi: 10.1158/1541-7786.MCR-17-0256. Epub 2017 Sep 19.
• [11] MicroRNA response to hypoxic stress in soft tissue sarcoma cells: microRNA mediated regulation of HIF3.BMC Cancer. 2014 Jun 13;14:429. doi: 10.1186/1471-2407-14-429.
• [12] Increase in proapoptotic activity of inhibitory PAS domain protein via phosphorylation by MK2.FEBS J. 2017 Dec;284(23):4115-4127. doi: 10.1111/febs.14300. Epub 2017 Nov 13.
• [13] Microarray detection of gene overexpression in primary spontaneous pneumothorax.Exp Lung Res. 2010 Aug;36(6):323-30. doi: 10.3109/01902141003628579.
• [14] Molecular profiling of thymoma with myasthenia gravis: Risk factors of developing myasthenia gravis in thymoma patients.Lung Cancer. 2020 Jan;139:157-164. doi: 10.1016/j.lungcan.2019.11.007. Epub 2019 Nov 15.
• [15] Interaction between obesity and the Hypoxia Inducible Factor 3 Alpha Subunit rs3826795 polymorphism in relation with plasma alanine aminotransferase.BMC Med Genet. 2017 Jul 28;18(1):80. doi: 10.1186/s12881-017-0437-0.
• [16] 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.
• [17] 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.
• [18] PGK1 induction by a hydrogen peroxide treatment is suppressed by antioxidants in human colon carcinoma cells. Biosci Biotechnol Biochem. 2008 Jul;72(7):1799-808. doi: 10.1271/bbb.80079. Epub 2008 Jul 7.
• [19] 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.
• [20] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [21] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [22] Isoproterenol effects evaluated in heart slices of human and rat in comparison to rat heart in vivo. Toxicol Appl Pharmacol. 2014 Jan 15;274(2):302-12.
• [23] 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.
• [24] 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.
• [25] Identification of chemical compounds that induce HIF-1alpha activity. Toxicol Sci. 2009 Nov;112(1):153-63.
• [26] 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.