Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKED2XN)

• DOT Name: E3 ubiquitin-protein ligase SIAH2 (SIAH2)
• Synonyms: EC 2.3.2.27; RING-type E3 ubiquitin transferase SIAH2; Seven in absentia homolog 2; Siah-2; hSiah2
• Gene Name: SIAH2
• Related Disease:
  Acute lymphocytic leukaemia
  Idiopathic thrombocytopenic purpura
  Lymphoid leukemia
  Breast cancer
  Breast carcinoma
  Castration-resistant prostate carcinoma
  Cerebral palsy
  Ductal carcinoma
  Estrogen-receptor positive breast cancer
  Glioblastoma multiforme
  Hepatocellular carcinoma
  Inflammatory breast cancer
  Isolated cleft palate
  Lentivirus infection
  Leukemia
  Lung cancer
  Lung carcinoma
  Myocardial infarction
  Non-small-cell lung cancer
  Oral cancer
  Prostate adenocarcinoma
  Prostate carcinoma
  Prostate neoplasm
  Advanced cancer
  Gastric cancer
  Hypoglycemia
  Lung adenocarcinoma
  Lung squamous cell carcinoma
  Stomach cancer
  Breast neoplasm
  Ductal breast carcinoma in situ
  Melanoma
  Neoplasm
  Prostate cancer
• UniProt ID: SIAH2_HUMAN
• PDB ID: 5H9M
• EC Number: 2.3.2.27
• Pfam ID: PF21362 ; PF03145 ; PF21361
• Sequence:
  MSRPSSTGPSANKPCSKQPPPQPQHTPSPAAPPAAATISAAGPGSSAVPAAAAVISGPGG
  GGGAGPVSPQHHELTSLFECPVCFDYVLPPILQCQAGHLVCNQCRQKLSCCPTCRGALTP
  SIRNLAMEKVASAVLFPCKYATTGCSLTLHHTEKPEHEDICEYRPYSCPCPGASCKWQGS
  LEAVMSHLMHAHKSITTLQGEDIVFLATDINLPGAVDWVMMQSCFGHHFMLVLEKQEKYE
  GHQQFFAIVLLIGTRKQAENFAYRLELNGNRRRLTWEATPRSIHDGVAAAIMNSDCLVFD
  TAIAHLFADNGNLGINVTISTCCP
• Function: E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 complexes. Triggers the ubiquitin-mediated degradation of many substrates, including proteins involved in transcription regulation (GPS2, POU2AF1, PML, NCOR1), a cell surface receptor (DCC), an antiapoptotic protein (BAG1), and a protein involved in synaptic vesicle function in neurons (SYP). Mediates ubiquitination and proteasomal degradation of DYRK2 in response to hypoxia. It is thereby involved in apoptosis, tumor suppression, cell cycle, transcription and signaling processes. Has some overlapping function with SIAH1. Triggers the ubiquitin-mediated degradation of TRAF2, whereas SIAH1 does not. Promotes monoubiquitination of SNCA. Regulates cellular clock function via ubiquitination of the circadian transcriptional repressors NR1D1 and NR1D2 leading to their proteasomal degradation. Plays an important role in mediating the rhythmic degradation/clearance of NR1D1 and NR1D2 contributing to their circadian profile of protein abundance. Mediates ubiquitination and degradation of EGLN2 and EGLN3 in response to the unfolded protein response (UPR), leading to their degradation and subsequent stabilization of ATF4. Also part of the Wnt signaling pathway in which it mediates the Wnt-induced ubiquitin-mediated proteasomal degradation of AXIN1.
• Tissue Specificity: Widely expressed at low level.
• Reactome Pathway:
  Ub-specific processing proteases (R-HSA-5689880)
  Amyloid fiber formation (R-HSA-977225)
  Antigen processing (R-HSA-983168)
  Netrin-1 signaling (R-HSA-373752)

Molecular Interaction Atlas (MIA) of This DOT

34 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute lymphocytic leukaemia	DISPX75S	Definitive	Biomarker	[1]
Idiopathic thrombocytopenic purpura	DISFKGJU	Definitive	Altered Expression	[1]
Lymphoid leukemia	DIS65TYQ	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Biomarker	[3]
Cerebral palsy	DIS82ODL	Strong	Altered Expression	[4]
Ductal carcinoma	DIS15EA5	Strong	Altered Expression	[2]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Genetic Variation	[5]
Glioblastoma multiforme	DISK8246	Strong	Altered Expression	[6]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[7]
Inflammatory breast cancer	DIS3QRWA	Strong	Altered Expression	[2]
Isolated cleft palate	DISV80CD	Strong	Altered Expression	[4]
Lentivirus infection	DISX17PY	Strong	Biomarker	[8]
Leukemia	DISNAKFL	Strong	Altered Expression	[9]
Lung cancer	DISCM4YA	Strong	Biomarker	[10]
Lung carcinoma	DISTR26C	Strong	Biomarker	[10]
Myocardial infarction	DIS655KI	Strong	Biomarker	[11]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[12]
Oral cancer	DISLD42D	Strong	Biomarker	[13]
Prostate adenocarcinoma	DISBZYU8	Strong	Altered Expression	[14]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[15]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[16]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[17]
Gastric cancer	DISXGOUK	moderate	Biomarker	[18]
Hypoglycemia	DISRCKR7	moderate	Biomarker	[19]
Lung adenocarcinoma	DISD51WR	moderate	Altered Expression	[10]
Lung squamous cell carcinoma	DISXPIBD	moderate	Altered Expression	[10]
Stomach cancer	DISKIJSX	moderate	Biomarker	[18]
Breast neoplasm	DISNGJLM	Limited	Altered Expression	[20]
Ductal breast carcinoma in situ	DISLCJY7	Limited	Altered Expression	[21]
Melanoma	DIS1RRCY	Limited	Altered Expression	[22]
Neoplasm	DISZKGEW	Limited	Biomarker	[23]
Prostate cancer	DISF190Y	Limited	Altered Expression	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[24]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[31]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[41]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[25]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[26]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[27]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[28]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[29]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[30]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[32]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[33]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[34]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[35]
Aspirin	DM672AH	Approved	Aspirin decreases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[36]
Cidofovir	DMA13GD	Approved	Cidofovir affects the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[29]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[29]
Clodronate	DM9Y6X7	Approved	Clodronate increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[29]
Estrone	DM5T6US	Approved	Estrone increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[34]
Bexarotene	DMOBIKY	Approved	Bexarotene decreases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[37]
Mestranol	DMG3F94	Approved	Mestranol increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[34]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[38]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[40]
HEXESTROL	DM9AGWQ	Withdrawn from market	HEXESTROL increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[34]
ICI-164384	DMYN3WG	Terminated	ICI-164384 decreases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[42]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate decreases the expression of E3 ubiquitin-protein ligase SIAH2 (SIAH2).	[43]

References

• [1] The expression and function of E3 ligase SIAH2 in acute T lymphoblastic leukemia.Leuk Res. 2016 Mar;42:28-36. doi: 10.1016/j.leukres.2016.01.013. Epub 2016 Jan 28.
• [2] Overexpression of seven in absentia homolog 2 protein in human breast cancer tissues is associated with the promotion of tumor cell malignant behavior in in vitro.Oncol Rep. 2016 Sep;36(3):1301-12. doi: 10.3892/or.2016.4976. Epub 2016 Jul 25.
• [3] Commentary on "the E3 ubiquitin ligase Siah2 contributes to castration-resistant prostate cancer by regulation of androgen receptor transcriptional activity." Qi J, Tripathi M, Mishra R, Sahgal N, Fazli L, Ettinger S, Placzek WJ, Claps G, Chung LW, Bowtell D, Gleave M, Bhowmick N, Ronai ZA, Signal Transduction Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.: Cancer Cell 2013;23(6):332-46.Urol Oncol. 2014 Feb;32(2):210-1. doi: 10.1016/j.urolonc.2013.08.020.
• [4] Inhibition of Siah2 Ubiquitin Ligase by Vitamin K3 Attenuates Chronic Myeloid Leukemia Chemo-Resistance in Hypoxic Microenvironment.Med Sci Monit. 2018 Feb 5;24:727-735. doi: 10.12659/msm.908553.
• [5] A common variant in the SIAH2 locus is associated with estrogen receptor-positive breast cancer in the Chinese Han population.PLoS One. 2013 Nov 11;8(11):e79365. doi: 10.1371/journal.pone.0079365. eCollection 2013.
• [6] The SIAH1-HIPK2-p53ser46 Damage Response Pathway is Involved in Temozolomide-Induced Glioblastoma Cell Death.Mol Cancer Res. 2019 May;17(5):1129-1141. doi: 10.1158/1541-7786.MCR-18-1306. Epub 2019 Feb 22.
• [7] Nuclear accumulation of seven in absentia homologue-2 supports motility and proliferation of liver cancer cells.Int J Cancer. 2012 Nov 1;131(9):2016-26. doi: 10.1002/ijc.27473. Epub 2012 Mar 27.
• [8] Effect of disrupting seven-in-absentia homolog 2 function on lung cancer cell growth.J Natl Cancer Inst. 2008 Nov 19;100(22):1606-29. doi: 10.1093/jnci/djn365. Epub 2008 Nov 11.
• [9] The coiled-coil domain is the structural determinant for mammalian homologues of Drosophila Sina-mediated degradation of promyelocytic leukemia protein and other tripartite motif proteins by the proteasome.J Biol Chem. 2004 Feb 13;279(7):5374-9. doi: 10.1074/jbc.M306407200. Epub 2003 Nov 25.
• [10] The Expression of the Ubiquitin Ligase SIAH2 (Seven In Absentia Homolog 2) Is Increased in Human Lung Cancer.PLoS One. 2015 Nov 18;10(11):e0143376. doi: 10.1371/journal.pone.0143376. eCollection 2015.
• [11] Fine-tuning of Drp1/Fis1 availability by AKAP121/Siah2 regulates mitochondrial adaptation to hypoxia.Mol Cell. 2011 Nov 18;44(4):532-44. doi: 10.1016/j.molcel.2011.08.045.
• [12] MiR-30 Family Potentially Targeting PI3K-SIAH2 Predicted Interaction Network Represents a Novel Putative Theranostic Panel in Non-small Cell Lung Cancer.Front Genet. 2017 Feb 2;8:8. doi: 10.3389/fgene.2017.00008. eCollection 2017.
• [13] The E3 ubiquitin ligase SIAH2 is a prosurvival factor overexpressed in oral cancer.Anticancer Res. 2013 Nov;33(11):4965-73.
• [14] The Siah2-HIF-FoxA2 axis in prostate cancer ?new markers and therapeutic opportunities.Oncotarget. 2010 Sep;1(5):379-85. doi: 10.18632/oncotarget.171.
• [15] DHX15 promotes prostate cancer progression by stimulating Siah2-mediated ubiquitination of androgen receptor.Oncogene. 2018 Feb 1;37(5):638-650. doi: 10.1038/onc.2017.371. Epub 2017 Oct 9.
• [16] The Steroidogenic Enzyme AKR1C3 Regulates Stability of the Ubiquitin Ligase Siah2 in Prostate Cancer Cells.J Biol Chem. 2015 Aug 21;290(34):20865-20879. doi: 10.1074/jbc.M115.662155. Epub 2015 Jul 9.
• [17] Phylogenetic analysis of the SINA/SIAH ubiquitin E3 ligase family in Metazoa.BMC Evol Biol. 2017 Aug 7;17(1):182. doi: 10.1186/s12862-017-1024-x.
• [18] Testin and filamin-C downregulation by acetylated Siah2 increases invasiveness of Helicobacter pylori-infected gastric cancer cells.Int J Biochem Cell Biol. 2018 Oct;103:14-24. doi: 10.1016/j.biocel.2018.07.012. Epub 2018 Jul 29.
• [19] Altered Nrf2 signaling mediates hypoglycemia-induced blood-brain barrier endothelial dysfunction in vitro.PLoS One. 2015 Mar 25;10(3):e0122358. doi: 10.1371/journal.pone.0122358. eCollection 2015.
• [20] Hypoxia regulates Hippo signalling through the SIAH2 ubiquitin E3 ligase.Nat Cell Biol. 2015 Jan;17(1):95-103. doi: 10.1038/ncb3073. Epub 2014 Dec 1.
• [21] The expression of the ubiquitin ligase SIAH2 (seven in absentia homolog 2) is mediated through gene copy number in breast cancer and is associated with a basal-like phenotype and p53 expression.Breast Cancer Res. 2011 Feb 9;13(1):R19. doi: 10.1186/bcr2828.
• [22] Identification and characterization of small molecule inhibitors of the ubiquitin ligases Siah1/2 in melanoma and prostate cancer cells.Cancer Lett. 2019 May 1;449:145-162. doi: 10.1016/j.canlet.2019.02.012. Epub 2019 Feb 14.
• [23] The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression.Nat Commun. 2019 Mar 4;10(1):1034. doi: 10.1038/s41467-019-08618-y.
• [24] 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.
• [25] 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.
• [26] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [27] 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.
• [28] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [29] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [30] Downregulation of SIAH2, an ubiquitin E3 ligase, is associated with resistance to endocrine therapy in breast cancer. Breast Cancer Res Treat. 2009 Jul;116(2):263-71. doi: 10.1007/s10549-008-0125-z. Epub 2008 Jul 16.
• [31] 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.
• [32] Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. doi: 10.1007/s00394-004-0503-1. Epub 2004 Apr 30.
• [33] 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.
• [34] Moving toward integrating gene expression profiling into high-throughput testing: a gene expression biomarker accurately predicts estrogen receptor alpha modulation in a microarray compendium. Toxicol Sci. 2016 May;151(1):88-103.
• [35] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [36] Expression profile analysis of human peripheral blood mononuclear cells in response to aspirin. Arch Immunol Ther Exp (Warsz). 2005 Mar-Apr;53(2):151-8.
• [37] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [38] 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.
• [39] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [40] 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.
• [41] 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.
• [42] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [43] Comparison of the global gene expression profiles produced by methylparaben, n-butylparaben and 17beta-oestradiol in MCF7 human breast cancer cells. J Appl Toxicol. 2007 Jan-Feb;27(1):67-77. doi: 10.1002/jat.1200.