Details of Drug Off-Target (DOT)

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

• DOT Name: E3 SUMO-protein ligase PIAS1 (PIAS1)
• Synonyms: EC 2.3.2.-; DEAD/H box-binding protein 1; E3 SUMO-protein transferase PIAS1; Gu-binding protein; GBP; Protein inhibitor of activated STAT protein 1; RNA helicase II-binding protein
• Gene Name: PIAS1
• Related Disease:
  Non-insulin dependent diabetes
  Advanced cancer
  Atopic dermatitis
  B-cell neoplasm
  Behcet disease
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Chronic eosinophilic leukemia
  Cystic fibrosis
  Focal segmental glomerulosclerosis
  Hepatocellular carcinoma
  Huntington disease
  Hyperaldosteronism
  Inflammatory bowel disease
  leukaemia
  Leukemia
  Lung adenocarcinoma
  Neoplasm
  Nephronophthisis
  Non-small-cell lung cancer
  Obesity
  Pneumonia
  Pneumonitis
  Polyp
  Promyelocytic leukaemia
  Prostate cancer
  Prostate carcinoma
  Skin disease
  Transitional cell carcinoma
  Urothelial carcinoma
  Coronary atherosclerosis
  Hypoglycemia
  Myocardial ischemia
  Gastric cancer
  Hepatitis C virus infection
  Stomach cancer
• UniProt ID: PIAS1_HUMAN
• PDB ID: 1V66
• EC Number: 2.3.2.-
• Pfam ID: PF14324 ; PF02891
• Sequence:
  MADSAELKQMVMSLRVSELQVLLGYAGRNKHGRKHELLTKALHLLKAGCSPAVQMKIKEL
  YRRRFPQKIMTPADLSIPNVHSSPMPATLSPSTIPQLTYDGHPASSPLLPVSLLGPKHEL
  ELPHLTSALHPVHPDIKLQKLPFYDLLDELIKPTSLASDNSQRFRETCFAFALTPQQVQQ
  ISSSMDISGTKCDFTVQVQLRFCLSETSCPQEDHFPPNLCVKVNTKPCSLPGYLPPTKNG
  VEPKRPSRPINITSLVRLSTTVPNTIVVSWTAEIGRNYSMAVYLVKQLSSTVLLQRLRAK
  GIRNPDHSRALIKEKLTADPDSEIATTSLRVSLLCPLGKMRLTIPCRALTCSHLQCFDAT
  LYIQMNEKKPTWVCPVCDKKAPYEHLIIDGLFMEILKYCTDCDEIQFKEDGTWAPMRSKK
  EVQEVSASYNGVDGCLSSTLEHQVASHHQSSNKNKKVEVIDLTIDSSSDEEEEEPSAKRT
  CPSLSPTSPLNNKGILSLPHQASPVSRTPSLPAVDTSYINTSLIQDYRHPFHMTPMPYDL
  QGLDFFPFLSGDNQHYNTSLLAAAAAAVSDDQDLLHSSRFFPYTSSQMFLDQLSAGGSTS
  LPTTNGSSSGSNSSLVSSNSLRESHSHTVTNRSSTDTASIFGIIPDIISLD
• 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, the p53 pathway and the steroid hormone signaling pathway. In vitro, binds A/T-rich DNA. The effects of this transcriptional coregulation, transactivation or silencing, may vary depending upon the biological context. Sumoylates PML (at'Lys-65' and 'Lys-160') and PML-RAR and promotes their ubiquitin-mediated degradation. PIAS1-mediated sumoylation of PML promotes its interaction with CSNK2A1/CK2 which in turn promotes PML phosphorylation and degradation. Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation. Plays a dynamic role in adipogenesis by promoting the SUMOylation and degradation of CEBPB. Mediates the nuclear mobility and localization of MSX1 to the nuclear periphery, whereby MSX1 is brought into the proximity of target myoblast differentiation factor genes. Also required for the binding of MSX1 to the core enhancer region in target gene promoter regions, independent of its sumolyation activity. Capable of binding to the core enhancer region TAAT box in the MYOD1 gene promoter; (Microbial infection) Restricts Epstein-Barr virus (EBV) lytic replication by acting as an inhibitor for transcription factors involved in lytic gene expression. The virus can use apoptotic caspases to antagonize PIAS1-mediated restriction and express its lytic genes.
• Tissue Specificity: Expressed in numerous tissues with highest level in testis.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  JAK-STAT sig.ling pathway (hsa04630)
  Hepatitis C (hsa05160)
• Reactome Pathway:
  SUMOylation of transcription factors (R-HSA-3232118)
  SUMOylation of ubiquitinylation proteins (R-HSA-3232142)
  SUMOylation of transcription cofactors (R-HSA-3899300)
  SUMOylation of intracellular receptors (R-HSA-4090294)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  Formation of Incision Complex in GG-NER (R-HSA-5696395)
  Regulation of IFNG signaling (R-HSA-877312)
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[3]
B-cell neoplasm	DISVY326	Strong	Biomarker	[4]
Behcet disease	DISSYMBS	Strong	Genetic Variation	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[7]
Chronic eosinophilic leukemia	DISAJOUO	Strong	Biomarker	[8]
Cystic fibrosis	DIS2OK1Q	Strong	Altered Expression	[9]
Focal segmental glomerulosclerosis	DISJNHH0	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[11]
Huntington disease	DISQPLA4	Strong	Biomarker	[12]
Hyperaldosteronism	DIS3WGAL	Strong	Biomarker	[13]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[14]
leukaemia	DISS7D1V	Strong	Biomarker	[15]
Leukemia	DISNAKFL	Strong	Biomarker	[15]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[16]
Neoplasm	DISZKGEW	Strong	Biomarker	[17]
Nephronophthisis	DISXU4HY	Strong	Genetic Variation	[18]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[15]
Obesity	DIS47Y1K	Strong	Altered Expression	[19]
Pneumonia	DIS8EF3M	Strong	Altered Expression	[20]
Pneumonitis	DIS88E0K	Strong	Altered Expression	[20]
Polyp	DISRSLYF	Strong	Genetic Variation	[21]
Promyelocytic leukaemia	DISYGG13	Strong	Biomarker	[15]
Prostate cancer	DISF190Y	Strong	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[2]
Skin disease	DISDW8R6	Strong	Biomarker	[22]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[2]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[2]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[23]
Hypoglycemia	DISRCKR7	moderate	Biomarker	[24]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[23]
Gastric cancer	DISXGOUK	Limited	Biomarker	[25]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[26]
Stomach cancer	DISKIJSX	Limited	Biomarker	[25]

16 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 PIAS1 (PIAS1).	[27]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[28]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[29]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[22]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[31]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[31]
Acetic Acid, Glacial	DM4SJ5Y	Approved	Acetic Acid, Glacial increases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[32]
Motexafin gadolinium	DMEJKRF	Approved	Motexafin gadolinium increases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[32]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[33]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[38]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[39]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[40]
Forskolin	DM6ITNG	Investigative	Forskolin decreases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[40]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[41]
OXYBENZONE	DMMZYX6	Investigative	OXYBENZONE increases the expression of E3 SUMO-protein ligase PIAS1 (PIAS1).	[42]

4 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 increases the methylation of E3 SUMO-protein ligase PIAS1 (PIAS1).	[35]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 SUMO-protein ligase PIAS1 (PIAS1).	[36]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of E3 SUMO-protein ligase PIAS1 (PIAS1).	[37]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of E3 SUMO-protein ligase PIAS1 (PIAS1).	[37]

References

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• [16] Identification of the targets of hematoporphyrin derivative in lung adenocarcinoma using integrated network analysis.Biol Res. 2019 Feb 4;52(1):4. doi: 10.1186/s40659-019-0213-z.
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• [21] Correlation of dyslipidemias and gallbladder polyps-A large retrospective study among Chinese population.Asian J Surg. 2020 Jan;43(1):181-185. doi: 10.1016/j.asjsur.2019.01.013. Epub 2019 Mar 15.
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• [23] PIAS1 protects against myocardial ischemia-reperfusion injury by stimulating PPAR SUMOylation.BMC Cell Biol. 2018 Nov 12;19(1):24. doi: 10.1186/s12860-018-0176-x.
• [24] A role for exogenous GLP-1 in the management of postprandial hypoglycaemia after Roux-en-Y gastric bypass?.Eur J Endocrinol. 2019 Sep;181(3):C5-C8. doi: 10.1530/EJE-19-0473.
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• [32] Motexafin gadolinium and zinc induce oxidative stress responses and apoptosis in B-cell lymphoma lines. Cancer Res. 2005 Dec 15;65(24):11676-88.
• [33] 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.
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• [37] 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.
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• [39] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [40] Identification of genes targeted by the androgen and PKA signaling pathways in prostate cancer cells. Oncogene. 2006 Nov 23;25(55):7311-23.
• [41] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.
• [42] Chromatin modifiers: A new class of pollutants with potential epigenetic effects revealed by in vitro assays and transcriptomic analyses. Toxicology. 2023 Jan 15;484:153413. doi: 10.1016/j.tox.2022.153413. Epub 2022 Dec 26.