Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS9GZK5)

• DOT Name: Metalloreductase STEAP3 (STEAP3)
• Synonyms: EC 1.16.1.-; Dudulin-2; Six-transmembrane epithelial antigen of prostate 3; Tumor suppressor-activated pathway protein 6; hTSAP6; pHyde; hpHyde
• Gene Name: STEAP3
• Related Disease:
  Colorectal carcinoma
  Crohn disease
  Adult glioblastoma
  Glioblastoma multiforme
  Glioma
  Hepatocellular carcinoma
  Hypochromic microcytic anemia
  IRIDA syndrome
  Liver cirrhosis
  Renal cell carcinoma
  Severe congenital hypochromic anemia with ringed sideroblasts
  Prostate cancer
  Prostate carcinoma
• UniProt ID: STEA3_HUMAN
• PDB ID: 2VNS; 2VQ3
• EC Number: 1.16.1.-
• Pfam ID: PF03807 ; PF01794
• Sequence:
  MPEEMDKPLISLHLVDSDSSLAKVPDEAPKVGILGSGDFARSLATRLVGSGFKVVVGSRN
  PKRTARLFPSAAQVTFQEEAVSSPEVIFVAVFREHYSSLCSLSDQLAGKILVDVSNPTEQ
  EHLQHRESNAEYLASLFPTCTVVKAFNVISAWTLQAGPRDGNRQVPICGDQPEAKRAVSE
  MALAMGFMPVDMGSLASAWEVEAMPLRLLPAWKVPTLLALGLFVCFYAYNFVRDVLQPYV
  QESQNKFFKLPVSVVNTTLPCVAYVLLSLVYLPGVLAAALQLRRGTKYQRFPDWLDHWLQ
  HRKQIGLLSFFCAALHALYSFCLPLRRAHRYDLVNLAVKQVLANKSHLWVEEEVWRMEIY
  LSLGVLALGTLSLLAVTSLPSIANSLNWREFSFVQSSLGFVALVLSTLHTLTYGWTRAFE
  ESRYKFYLPPTFTLTLLVPCVVILAKALFLLPCISRRLARIRRGWERESTIKFTLPTDHA
  LAEKTSHV
• Function: Integral membrane protein that functions as a NADPH-dependent ferric-chelate reductase, using NADPH from one side of the membrane to reduce a Fe(3+) chelate that is bound on the other side of the membrane. Mediates sequential transmembrane electron transfer from NADPH to FAD and onto heme, and finally to the Fe(3+) chelate. Can also reduce Cu(2+) to Cu(1+). Mediates efficient transferrin-dependent iron uptake in erythroid cells. May play a role downstream of p53/TP53 to interface apoptosis and cell cycle progression. Indirectly involved in exosome secretion by facilitating the secretion of proteins such as TCTP.
• Tissue Specificity: Expressed in adult bone marrow, placenta, liver, skeletal muscle and pancreas. Down-regulated in hepatocellular carcinoma.
• KEGG Pathway:
  p53 sig.ling pathway (hsa04115)
  Ferroptosis (hsa04216)
• Reactome Pathway:
  CDC42 GTPase cycle (R-HSA-9013148)
  RHOD GTPase cycle (R-HSA-9013405)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOJ GTPase cycle (R-HSA-9013409)
  RHOF GTPase cycle (R-HSA-9035034)
  Transferrin endocytosis and recycling (R-HSA-917977)
  TP53 Regulates Transcription of Genes Involved in Cytochrome C Release (R-HSA-6803204)

Molecular Interaction Atlas (MIA) of This DOT

13 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal carcinoma	DIS5PYL0	Definitive	Altered Expression	[1]
Crohn disease	DIS2C5Q8	Definitive	Altered Expression	[2]
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[3]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[3]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Hypochromic microcytic anemia	DIS0RMTQ	Strong	Genetic Variation	[5]
IRIDA syndrome	DISPN8YW	Strong	Biomarker	[6]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[7]
Renal cell carcinoma	DISQZ2X8	Strong	Genetic Variation	[8]
Severe congenital hypochromic anemia with ringed sideroblasts	DIS7V020	Moderate	Autosomal dominant	[9]
Prostate cancer	DISF190Y	Limited	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[10]

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 Metalloreductase STEAP3 (STEAP3).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Metalloreductase STEAP3 (STEAP3).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Metalloreductase STEAP3 (STEAP3).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Metalloreductase STEAP3 (STEAP3).	[14]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Metalloreductase STEAP3 (STEAP3).	[15]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Metalloreductase STEAP3 (STEAP3).	[17]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Metalloreductase STEAP3 (STEAP3).	[18]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Metalloreductase STEAP3 (STEAP3).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Metalloreductase STEAP3 (STEAP3).	[20]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of Metalloreductase STEAP3 (STEAP3).	[21]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Metalloreductase STEAP3 (STEAP3).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Metalloreductase STEAP3 (STEAP3).	[20]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Metalloreductase STEAP3 (STEAP3).	[15]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Metalloreductase STEAP3 (STEAP3).	[24]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Metalloreductase STEAP3 (STEAP3).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Metalloreductase STEAP3 (STEAP3).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Metalloreductase STEAP3 (STEAP3).	[28]

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 Metalloreductase STEAP3 (STEAP3).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Metalloreductase STEAP3 (STEAP3).	[23]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Metalloreductase STEAP3 (STEAP3).	[25]

References

• [1] Analysis of exosome release and its prognostic value in human colorectal cancer.Genes Chromosomes Cancer. 2012 Apr;51(4):409-18. doi: 10.1002/gcc.21926.
• [2] Influence of smoking on colonic gene expression profile in Crohn's disease.PLoS One. 2009 Jul 15;4(7):e6210. doi: 10.1371/journal.pone.0006210.
• [3] Six-Transmembrane Epithelial Antigen of Prostate 3 Predicts Poor Prognosis and Promotes Glioblastoma Growth and Invasion.Neoplasia. 2018 Jun;20(6):543-554. doi: 10.1016/j.neo.2018.04.002. Epub 2018 May 3.
• [4] Copper transporters are responsible for copper isotopic fractionation in eukaryotic cells.Sci Rep. 2017 Mar 17;7:44533. doi: 10.1038/srep44533.
• [5] Identification of a Steap3 endosomal targeting motif essential for normal iron metabolism.Blood. 2009 Feb 19;113(8):1805-8. doi: 10.1182/blood-2007-11-120402. Epub 2008 Oct 27.
• [6] A novel type of congenital hypochromic anemia associated with a nonsense mutation in the STEAP3/TSAP6 gene. Blood. 2011 Dec 15;118(25):6660-6. doi: 10.1182/blood-2011-01-329011. Epub 2011 Oct 26.
• [7] Global gene repression in hepatocellular carcinoma and fetal liver, and suppression of dudulin-2 mRNA as a possible marker for the cirrhosis-to-tumor transition.J Hepatol. 2005 Jun;42(6):860-9. doi: 10.1016/j.jhep.2005.01.027. Epub 2005 Apr 11.
• [8] Sex specific associations in genome wide association analysis of renal cell carcinoma.Eur J Hum Genet. 2019 Oct;27(10):1589-1598. doi: 10.1038/s41431-019-0455-9. Epub 2019 Jun 23.
• [9] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [10] Adenoviral-mediated pHyde gene transfer and cisplatin additively inhibit human prostate cancer growth by enhancing apoptosis.Prostate. 2009 Feb 15;69(3):234-48. doi: 10.1002/pros.20867.
• [11] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [12] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] 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.
• [17] 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.
• [18] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [19] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] Identification of biomarkers and outcomes of endocrine disruption in human ovarian cortex using In Vitro Models. Toxicology. 2023 Feb;485:153425. doi: 10.1016/j.tox.2023.153425. Epub 2023 Jan 5.
• [22] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [25] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [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] 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.
• [28] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.