Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3TWH9R)

DOT Name E3 SUMO-protein ligase PIAS3 (PIAS3)
Synonyms EC 2.3.2.-; E3 SUMO-protein transferase PIAS3; Protein inhibitor of activated STAT protein 3
Gene Name PIAS3
Related Disease
Glioma ( )
Acute erythroid leukemia ( )
Adult T-cell leukemia/lymphoma ( )
Alcoholic cirrhosis of liver ( )
Brain neoplasm ( )
Cervical cancer ( )
Essential thrombocythemia ( )
Estrogen-receptor positive breast cancer ( )
Gastric cancer ( )
Hepatitis C virus infection ( )
Liver cirrhosis ( )
Lung cancer ( )
Lung carcinoma ( )
Lung neoplasm ( )
Lung squamous cell carcinoma ( )
Medulloblastoma ( )
Obesity ( )
Pancreatitis ( )
Precancerous condition ( )
Relapsing-remitting multiple sclerosis ( )
Squamous cell carcinoma ( )
Stomach cancer ( )
T-cell leukaemia ( )
Uterine cervix neoplasm ( )
Advanced cancer ( )
Colorectal carcinoma ( )
Adenocarcinoma ( )
Adult glioblastoma ( )
Bone osteosarcoma ( )
Breast cancer ( )
Breast carcinoma ( )
Cervical carcinoma ( )
Glioblastoma multiforme ( )
Mesothelioma ( )
Non-small-cell lung cancer ( )
Osteosarcoma ( )
Prostate cancer ( )
Prostate carcinoma ( )
Small lymphocytic lymphoma ( )
UniProt ID
PIAS3_HUMAN
3D Structure
Download
2D Sequence (FASTA)
Download
3D Structure (PDB)
Download
PDB ID
4MVT
EC Number
2.3.2.-
Pfam ID
PF14324 ; PF02891
Sequence
MAELGELKHMVMSFRVSELQVLLGFAGRNKSGRKHELLAKALHLLKSSCAPSVQMKIKEL
YRRRFPRKTLGPSDLSLLSLPPGTSPVGSPGPLAPIPPTLLAPGTLLGPKREVDMHPPLP
QPVHPDVTMKPLPFYEVYGELIRPTTLASTSSQRFEEAHFTFALTPQQVQQILTSREVLP
GAKCDYTIQVQLRFCLCETSCPQEDYFPPNLFVKVNGKLCPLPGYLPPTKNGAEPKRPSR
PINITPLARLSATVPNTIVVNWSSEFGRNYSLSVYLVRQLTAGTLLQKLRAKGIRNPDHS
RALIKEKLTADPDSEVATTSLRVSLMCPLGKMRLTVPCRALTCAHLQSFDAALYLQMNEK
KPTWTCPVCDKKAPYESLIIDGLFMEILSSCSDCDEIQFMEDGSWCPMKPKKEASEVCPP
PGYGLDGLQYSPVQGGDPSENKKKVEVIDLTIESSSDEEDLPPTKKHCSVTSAAIPALPG
SKGVLTSGHQPSSVLRSPAMGTLGGDFLSSLPLHEYPPAFPLGADIQGLDLFSFLQTESQ
HYGPSVITSLDEQDALGHFFQYRGTPSHFLGPLAPTLGSSHCSATPAPPPGRVSSIVAPG
GALREGHGGPLPSGPSLTGCRSDIISLD
Function
Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. Plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway and the steroid hormone signaling pathway. Involved in regulating STAT3 signaling via inhibiting STAT3 DNA-binding and suppressing cell growth. Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation. Sumoylates CCAR2 which promotes its interaction with SIRT1. Diminishes the sumoylation of ZFHX3 by preventing the colocalization of ZFHX3 with SUMO1 in the nucleus.
Tissue Specificity Widely expressed.
KEGG Pathway
Ubiquitin mediated proteolysis (hsa04120 )
JAK-STAT sig.ling pathway (hsa04630 )
Reactome Pathway
SUMOylation of transcription cofactors (R-HSA-3899300 )
SUMOylation of intracellular receptors (R-HSA-4090294 )
SUMOylation of DNA replication proteins (R-HSA-4615885 )
SUMOylation of immune response proteins (R-HSA-4755510 )
Formation of Incision Complex in GG-NER (R-HSA-5696395 )
SUMOylation of transcription factors (R-HSA-3232118 )

Molecular Interaction Atlas (MIA) of This DOT

39 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Glioma DIS5RPEH Definitive Biomarker [1]
Acute erythroid leukemia DISZFC1O Strong Biomarker [2]
Adult T-cell leukemia/lymphoma DIS882XU Strong Altered Expression [3]
Alcoholic cirrhosis of liver DISQ1WRT Strong Altered Expression [4]
Brain neoplasm DISY3EKS Strong Altered Expression [5]
Cervical cancer DISFSHPF Strong Biomarker [6]
Essential thrombocythemia DISWWK11 Strong Altered Expression [7]
Estrogen-receptor positive breast cancer DIS1H502 Strong Altered Expression [8]
Gastric cancer DISXGOUK Strong Altered Expression [9]
Hepatitis C virus infection DISQ0M8R Strong Altered Expression [4]
Liver cirrhosis DIS4G1GX Strong Altered Expression [4]
Lung cancer DISCM4YA Strong Biomarker [10]
Lung carcinoma DISTR26C Strong Biomarker [10]
Lung neoplasm DISVARNB Strong Altered Expression [11]
Lung squamous cell carcinoma DISXPIBD Strong Altered Expression [12]
Medulloblastoma DISZD2ZL Strong Altered Expression [13]
Obesity DIS47Y1K Strong Altered Expression [14]
Pancreatitis DIS0IJEF Strong Altered Expression [15]
Precancerous condition DISV06FL Strong Biomarker [16]
Relapsing-remitting multiple sclerosis DISSXFCF Strong Altered Expression [17]
Squamous cell carcinoma DISQVIFL Strong Biomarker [6]
Stomach cancer DISKIJSX Strong Altered Expression [9]
T-cell leukaemia DISJ6YIF Strong Biomarker [3]
Uterine cervix neoplasm DIS0BYVV Strong Biomarker [18]
Advanced cancer DISAT1Z9 moderate Biomarker [16]
Colorectal carcinoma DIS5PYL0 moderate Altered Expression [19]
Adenocarcinoma DIS3IHTY Limited Altered Expression [20]
Adult glioblastoma DISVP4LU Limited Biomarker [21]
Bone osteosarcoma DIST1004 Limited Biomarker [22]
Breast cancer DIS7DPX1 Limited Biomarker [23]
Breast carcinoma DIS2UE88 Limited Biomarker [23]
Cervical carcinoma DIST4S00 Limited Altered Expression [24]
Glioblastoma multiforme DISK8246 Limited Biomarker [21]
Mesothelioma DISKWK9M Limited Altered Expression [25]
Non-small-cell lung cancer DIS5Y6R9 Limited Altered Expression [26]
Osteosarcoma DISLQ7E2 Limited Biomarker [22]
Prostate cancer DISF190Y Limited Altered Expression [27]
Prostate carcinoma DISMJPLE Limited Altered Expression [27]
Small lymphocytic lymphoma DIS30POX Limited Biomarker [28]
------------------------------------------------------------------------------------
⏷ Show the Full List of 39 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
13 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 E3 SUMO-protein ligase PIAS3 (PIAS3). [29]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of E3 SUMO-protein ligase PIAS3 (PIAS3). [30]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of E3 SUMO-protein ligase PIAS3 (PIAS3). [31]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of E3 SUMO-protein ligase PIAS3 (PIAS3). [32]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of E3 SUMO-protein ligase PIAS3 (PIAS3). [33]
Cisplatin DMRHGI9 Approved Cisplatin increases the expression of E3 SUMO-protein ligase PIAS3 (PIAS3). [34]
Vorinostat DMWMPD4 Approved Vorinostat decreases the expression of E3 SUMO-protein ligase PIAS3 (PIAS3). [35]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of E3 SUMO-protein ligase PIAS3 (PIAS3). [36]
Digitoxin DMWVIGP Approved Digitoxin increases the expression of E3 SUMO-protein ligase PIAS3 (PIAS3). [37]
Urethane DM7NSI0 Phase 4 Urethane increases the expression of E3 SUMO-protein ligase PIAS3 (PIAS3). [38]
Resveratrol DM3RWXL Phase 3 Resveratrol increases the expression of E3 SUMO-protein ligase PIAS3 (PIAS3). [18]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of E3 SUMO-protein ligase PIAS3 (PIAS3). [41]
Milchsaure DM462BT Investigative Milchsaure decreases the expression of E3 SUMO-protein ligase PIAS3 (PIAS3). [42]
------------------------------------------------------------------------------------
⏷ Show the Full List of 13 Drug(s)
1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
TAK-243 DM4GKV2 Phase 1 TAK-243 increases the sumoylation of E3 SUMO-protein ligase PIAS3 (PIAS3). [40]
------------------------------------------------------------------------------------

References

1 Sumoylation of vimentin354 is associated with PIAS3 inhibition of glioma cell migration.Oncotarget. 2010 Nov;1(7):620-627. doi: 10.18632/oncotarget.196.
2 Transcriptional activity of erythroid Kruppel-like factor (EKLF/KLF1) modulated by PIAS3 (protein inhibitor of activated STAT3).J Biol Chem. 2015 Apr 10;290(15):9929-40. doi: 10.1074/jbc.M114.610246. Epub 2015 Feb 24.
3 Down-regulation of SHP1 and up-regulation of negative regulators of JAK/STAT signaling in HTLV-1 transformed cell lines and freshly transformed human peripheral blood CD4+ T-cells.Leuk Res. 2004 Jan;28(1):71-82. doi: 10.1016/s0145-2126(03)00158-9.
4 Deficient Stat3 DNA-binding is associated with high Pias3 expression and a positive anti-apoptotic balance in human end-stage alcoholic and hepatitis C cirrhosis.J Hepatol. 2005 Oct;43(4):687-95. doi: 10.1016/j.jhep.2005.03.024.
5 Differential PIAS3 expression in human malignancy.Oncol Rep. 2004 Jun;11(6):1319-24.
6 PIAS3, SHP2 and SOCS3 Expression patterns in Cervical Cancers: Relevance with activation and resveratrol-caused inactivation of STAT3 signaling.Gynecol Oncol. 2015 Dec;139(3):529-35. doi: 10.1016/j.ygyno.2015.09.087. Epub 2015 Oct 4.
7 Decreased expression of PIAS1 and PIAS3 in essential thrombocythemia patients.Genet Mol Res. 2013 Nov 18;12(4):5617-22. doi: 10.4238/2013.November.18.10.
8 Reconstruction of nuclear receptor network reveals that NR2E3 is a novel upstream regulator of ESR1 in breast cancer.EMBO Mol Med. 2012 Jan;4(1):52-67. doi: 10.1002/emmm.201100187. Epub 2011 Dec 15.
9 MicroRNA-18a modulates STAT3 activity through negative regulation of PIAS3 during gastric adenocarcinogenesis.Br J Cancer. 2013 Feb 19;108(3):653-61. doi: 10.1038/bjc.2012.587. Epub 2013 Jan 15.
10 PIAS3 activates the intrinsic apoptotic pathway in non-small cell lung cancer cells independent of p53 status.Int J Cancer. 2014 Mar 1;134(5):1045-54. doi: 10.1002/ijc.28448. Epub 2013 Sep 23.
11 Overexpression of PIAS3 suppresses cell growth and restores the drug sensitivity of human lung cancer cells in association with PI3-K/Akt inactivation.Neoplasia. 2006 Oct;8(10):817-25. doi: 10.1593/neo.06409.
12 PIAS3 expression in squamous cell lung cancer is low and predicts overall survival.Cancer Med. 2015 Mar;4(3):325-32. doi: 10.1002/cam4.372. Epub 2015 Jan 9.
13 SHP2, SOCS3 and PIAS3 Expression Patterns in Medulloblastomas: Relevance to STAT3 Activation and Resveratrol-Suppressed STAT3 Signaling.Nutrients. 2016 Dec 27;9(1):3. doi: 10.3390/nu9010003.
14 A role for protein inhibitor of activated STAT1 (PIAS1) in lipogenic regulation through SUMOylation-independent suppression of liver X receptors.J Biol Chem. 2012 Nov 2;287(45):37973-85. doi: 10.1074/jbc.M112.403139. Epub 2012 Sep 11.
15 RNA-Seq Analyses of the Role of miR-21 in Acute Pancreatitis.Cell Physiol Biochem. 2018;51(5):2198-2211. doi: 10.1159/000495866. Epub 2018 Dec 7.
16 STAT3/PIAS3 Levels Serve as "Early Signature" Genes in the Development of High-Grade Serous Carcinoma from the Fallopian Tube.Cancer Res. 2018 Apr 1;78(7):1739-1750. doi: 10.1158/0008-5472.CAN-17-1671. Epub 2018 Jan 16.
17 Increased expression of mir-301a in PBMCs of patients with relapsing-remitting multiple sclerosis is associated with reduced NKRF and PIAS3 expression levels and disease activity.J Neuroimmunol. 2018 Dec 15;325:79-86. doi: 10.1016/j.jneuroim.2018.10.002. Epub 2018 Oct 4.
18 Biological significance and therapeutic implication of resveratrol-inhibited Wnt, Notch and STAT3 signaling in cervical cancer cells. Genes Cancer. 2014 May;5(5-6):154-64. doi: 10.18632/genesandcancer.15.
19 PIAS3-mediated feedback loops promote chronic colitis-associated malignant transformation.Theranostics. 2018 Apr 30;8(11):3022-3037. doi: 10.7150/thno.23046. eCollection 2018.
20 Protein inhibitor of activated STAT3 expression in lung cancer.Mol Oncol. 2011 Jun;5(3):256-64. doi: 10.1016/j.molonc.2011.03.004. Epub 2011 Mar 30.
21 TRIM8 regulates stemness in glioblastoma through PIAS3-STAT3.Mol Oncol. 2017 Mar;11(3):280-294. doi: 10.1002/1878-0261.12034. Epub 2017 Feb 15.
22 MicroRNA-199a-5p promotes tumour growth by dual-targeting PIAS3 and p27 in human osteosarcoma.Sci Rep. 2017 Jan 25;7:41456. doi: 10.1038/srep41456.
23 The PIAS3-Smurf2 sumoylation pathway suppresses breast cancer organoid invasiveness.Oncotarget. 2017 Mar 28;8(13):21001-21014. doi: 10.18632/oncotarget.15471.
24 miR-199a-5p promotes proliferation and metastasis and epithelial-mesenchymal transition through targeting PIAS3 in cervical carcinoma.J Cell Biochem. 2019 Aug;120(8):13562-13572. doi: 10.1002/jcb.28631. Epub 2019 Apr 1.
25 Low PIAS3 expression in malignant mesothelioma is associated with increased STAT3 activation and poor patient survival.Clin Cancer Res. 2014 Oct 1;20(19):5124-32. doi: 10.1158/1078-0432.CCR-14-1233. Epub 2014 Aug 14.
26 Expression of STAT5, COX-2 and PIAS3 in correlation with NSCLC histhopathological features.PLoS One. 2014 Aug 19;9(8):e104265. doi: 10.1371/journal.pone.0104265. eCollection 2014.
27 N-terminal truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in prostate cancer cells.Int J Biochem Cell Biol. 2010 Dec;42(12):2037-46. doi: 10.1016/j.biocel.2010.09.008. Epub 2010 Sep 18.
28 Microenvironment regulates the expression of miR-21 and tumor suppressor genes PTEN, PIAS3 and PDCD4 through ZAP-70 in chronic lymphocytic leukemia.Sci Rep. 2017 Sep 25;7(1):12262. doi: 10.1038/s41598-017-12135-7.
29 Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
30 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
31 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.
32 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.
33 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
34 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
35 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.
36 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
37 Digitoxin promotes apoptosis and inhibits proliferation and migration by reducing HIF-1 and STAT3 in KRAS mutant human colon cancer cells. Chem Biol Interact. 2022 Jan 5;351:109729. doi: 10.1016/j.cbi.2021.109729. Epub 2021 Oct 28.
38 Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
39 Biological significance and therapeutic implication of resveratrol-inhibited Wnt, Notch and STAT3 signaling in cervical cancer cells. Genes Cancer. 2014 May;5(5-6):154-64. doi: 10.18632/genesandcancer.15.
40 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.
41 Gene expression profiling reveals novel regulation by bisphenol-A in estrogen receptor-alpha-positive human cells. Environ Res. 2006 Jan;100(1):86-92.
42 Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.