Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJLSC3V)

• DOT Name: E3 SUMO-protein ligase PIAS2 (PIAS2)
• Synonyms: EC 2.3.2.-; Androgen receptor-interacting protein 3; ARIP3; DAB2-interacting protein; DIP; E3 SUMO-protein transferase PIAS2; Msx-interacting zinc finger protein; Miz1; PIAS-NY protein; Protein inhibitor of activated STAT x; Protein inhibitor of activated STAT2
• Gene Name: PIAS2
• Related Disease:
  B-cell neoplasm
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  T-cell lymphoma
  Acute lymphocytic leukaemia
  B-cell lymphoma
  Carcinoma of esophagus
  Childhood acute lymphoblastic leukemia
  Childhood myelodysplastic syndrome
  Clear cell renal carcinoma
  Esophageal cancer
  Hepatitis C virus infection
  Melanoma
  Myelodysplastic syndrome
  Neoplasm
  Neoplasm of esophagus
  Renal cell carcinoma
  Parkinson disease
  Adult lymphoma
  Lymphoma
  Neuroblastoma
  Pediatric lymphoma
• UniProt ID: PIAS2_HUMAN
• PDB ID: 2ASQ; 4FO9
• EC Number: 2.3.2.-
• Pfam ID: PF14324 ; PF02891
• Sequence:
  MADFEELRNMVSSFRVSELQVLLGFAGRNKSGRKHDLLMRALHLLKSGCSPAVQIKIREL
  YRRRYPRTLEGLSDLSTIKSSVFSLDGGSSPVEPDLAVAGIHSLPSTSVTPHSPSSPVGS
  VLLQDTKPTFEMQQPSPPIPPVHPDVQLKNLPFYDVLDVLIKPTSLVQSSIQRFQEKFFI
  FALTPQQVREICISRDFLPGGRRDYTVQVQLRLCLAETSCPQEDNYPNSLCIKVNGKLFP
  LPGYAPPPKNGIEQKRPGRPLNITSLVRLSSAVPNQISISWASEIGKNYSMSVYLVRQLT
  SAMLLQRLKMKGIRNPDHSRALIKEKLTADPDSEIATTSLRVSLMCPLGKMRLTIPCRAV
  TCTHLQCFDAALYLQMNEKKPTWICPVCDKKAAYESLILDGLFMEILNDCSDVDEIKFQE
  DGSWCPMRPKKEAMKVSSQPCTKIESSSVLSKPCSVTVASEASKKKVDVIDLTIESSSDE
  EEDPPAKRKCIFMSETQSSPTKGVLMYQPSSVRVPSVTSVDPAAIPPSLTDYSVPFHHTP
  ISSMSSDLPGLDFLSLIPVDPQYCPPMFLDSLTSPLTASSTSVTTTSSHESSTHVSSSSS
  RSETGVITSSGSNIPDIISLD
• 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 coregulator in various cellular pathways, including the STAT pathway, the p53 pathway and the steroid hormone signaling pathway. The effects of this transcriptional coregulation, transactivation or silencing may vary depending upon the biological context and the PIAS2 isoform studied. However, it seems to be mostly involved in gene silencing. Binds to sumoylated ELK1 and enhances its transcriptional activity by preventing recruitment of HDAC2 by ELK1, thus reversing SUMO-mediated repression of ELK1 transactivation activity. Isoform PIAS2-beta, but not isoform PIAS2-alpha, promotes MDM2 sumoylation. Isoform PIAS2-alpha promotes PARK7 sumoylation. Isoform PIAS2-beta promotes NCOA2 sumoylation more efficiently than isoform PIAS2-alpha. Isoform PIAS2-alpha sumoylates PML at'Lys-65' and 'Lys-160'.
• Tissue Specificity: Mainly expressed in testis. Isoform 3 is expressed predominantly in adult testis, weakly in pancreas, embryonic testis and sperm, and at very low levels in other organs.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  JAK-STAT sig.ling pathway (hsa04630)
• Reactome Pathway:
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  SUMOylation of intracellular receptors (R-HSA-4090294)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Definitive	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Definitive	Biomarker	[2]
Ovarian cancer	DISZJHAP	Definitive	Biomarker	[2]
Ovarian neoplasm	DISEAFTY	Definitive	Biomarker	[2]
T-cell lymphoma	DISSXRTQ	Definitive	Altered Expression	[3]
Acute lymphocytic leukaemia	DISPX75S	Strong	Biomarker	[4]
B-cell lymphoma	DISIH1YQ	Strong	Genetic Variation	[5]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[6]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Biomarker	[4]
Childhood myelodysplastic syndrome	DISMN80I	Strong	Biomarker	[7]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[8]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[9]
Melanoma	DIS1RRCY	Strong	Biomarker	[10]
Myelodysplastic syndrome	DISYHNUI	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[11]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[6]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[8]
Parkinson disease	DISQVHKL	Disputed	Altered Expression	[12]
Adult lymphoma	DISK8IZR	Limited	Genetic Variation	[4]
Lymphoma	DISN6V4S	Limited	Genetic Variation	[4]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[13]
Pediatric lymphoma	DIS51BK2	Limited	Genetic Variation	[4]

8 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 E3 SUMO-protein ligase PIAS2 (PIAS2).	[14]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of E3 SUMO-protein ligase PIAS2 (PIAS2).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 SUMO-protein ligase PIAS2 (PIAS2).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of E3 SUMO-protein ligase PIAS2 (PIAS2).	[17]
APR-246	DMNFADH	Phase 2	APR-246 affects the expression of E3 SUMO-protein ligase PIAS2 (PIAS2).	[18]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of E3 SUMO-protein ligase PIAS2 (PIAS2).	[21]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of E3 SUMO-protein ligase PIAS2 (PIAS2).	[22]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of E3 SUMO-protein ligase PIAS2 (PIAS2).	[23]

2 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 decreases the methylation of E3 SUMO-protein ligase PIAS2 (PIAS2).	[19]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 SUMO-protein ligase PIAS2 (PIAS2).	[20]

References

• [1] The proto-oncoprotein KR-POK represses transcriptional activation of CDKN1A by MIZ-1 through competitive binding.Oncogene. 2012 Mar 15;31(11):1442-58. doi: 10.1038/onc.2011.331. Epub 2011 Aug 1.
• [2] Nac1 interacts with the POZ-domain transcription factor, Miz1.Biosci Rep. 2014 Jun 5;34(3):e00110. doi: 10.1042/BSR20140049.
• [3] The interaction between Myc and Miz1 is required to antagonize TGFbeta-dependent autocrine signaling during lymphoma formation and maintenance.Genes Dev. 2010 Jun 15;24(12):1281-94. doi: 10.1101/gad.585710.
• [4] Deletion of the Miz-1 POZ Domain Increases Efficacy of Cytarabine Treatment in T- and B-ALL/Lymphoma Mouse Models.Cancer Res. 2019 Aug 15;79(16):4184-4195. doi: 10.1158/0008-5472.CAN-18-3038. Epub 2019 Jul 4.
• [5] BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma.Proc Natl Acad Sci U S A. 2009 Jul 7;106(27):11294-9. doi: 10.1073/pnas.0903854106. Epub 2009 Jun 23.
• [6] Miz-1 promotes the proliferation of esophageal cancer cells via suppression of p21 and release of p21-arrested cyclinD1.Oncol Rep. 2016 Jun;35(6):3532-40. doi: 10.3892/or.2016.4731. Epub 2016 Apr 4.
• [7] Ribosomal protein L23 negatively regulates cellular apoptosis via the RPL23/Miz-1/c-Myc circuit in higher-risk myelodysplastic syndrome.Sci Rep. 2017 May 24;7(1):2323. doi: 10.1038/s41598-017-02403-x.
• [8] MicroRNA-34a suppresses malignant transformation by targeting c-Myc transcriptional complexes in human renal cell carcinoma.Carcinogenesis. 2012 Feb;33(2):294-300. doi: 10.1093/carcin/bgr286. Epub 2011 Dec 9.
• [9] Protein Inhibitor of Activated STAT2 Restricts HCV Replication by Modulating Viral Proteins Degradation.Viruses. 2017 Sep 30;9(10):285. doi: 10.3390/v9100285.
• [10] Humoral immune response against melanoma antigens induced by vaccination with cytokine gene-modified autologous tumor cells.Int J Cancer. 2004 Jan 10;108(2):307-13. doi: 10.1002/ijc.11537.
• [11] Mutant p53 potentiates the oncogenic effects of insulin by inhibiting the tumor suppressor DAB2IP.Proc Natl Acad Sci U S A. 2017 Jul 18;114(29):7623-7628. doi: 10.1073/pnas.1700996114. Epub 2017 Jun 30.
• [12] SUMOylation and ubiquitination reciprocally regulate -synuclein degradation and pathological aggregation.Proc Natl Acad Sci U S A. 2017 Dec 12;114(50):13176-13181. doi: 10.1073/pnas.1704351114. Epub 2017 Nov 27.
• [13] Destabilization of MYC/MYCN by the mitochondrial inhibitors, metaiodobenzylguanidine, metformin and phenformin.Int J Mol Med. 2014 Jan;33(1):35-42. doi: 10.3892/ijmm.2013.1545. Epub 2013 Nov 1.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] 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.
• [16] 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.
• [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] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
• [23] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.