Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTB7SVMZ)

• DOT Name: E3 SUMO-protein ligase PIAS4 (PIAS4)
• Synonyms: EC 2.3.2.27; PIASy; Protein inhibitor of activated STAT protein 4; Protein inhibitor of activated STAT protein gamma; PIAS-gamma
• Gene Name: PIAS4
• Related Disease:
  Advanced cancer
  Colon cancer
  Colon carcinoma
  Diabetic kidney disease
  Leukemia
  Lung cancer
  Lung carcinoma
  Myelodysplastic syndrome
  Neoplasm
  Non-small-cell lung cancer
  Pancreatic cancer
  Psoriasis
  Retinoblastoma
  Synovial sarcoma
  Von hippel-lindau disease
  Isolated congenital microcephaly
  Melanoma
  Childhood kidney Wilms tumor
  Nervous system inflammation
  Type-1/2 diabetes
  Wilms tumor
• UniProt ID: PIAS4_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF14324 ; PF02891
• Sequence:
  MAAELVEAKNMVMSFRVSDLQMLLGFVGRSKSGLKHELVTRALQLVQFDCSPELFKKIKE
  LYETRYAKKNSEPAPQPHRPLDPLTMHSTYDRAGAVPRTPLAGPNIDYPVLYGKYLNGLG
  RLPAKTLKPEVRLVKLPFFNMLDELLKPTELVPQNNEKLQESPCIFALTPRQVELIRNSR
  ELQPGVKAVQVVLRICYSDTSCPQEDQYPPNIAVKVNHSYCSVPGYYPSNKPGVEPKRPC
  RPINLTHLMYLSSATNRITVTWGNYGKSYSVALYLVRQLTSSELLQRLKTIGVKHPELCK
  ALVKEKLRLDPDSEIATTGVRVSLICPLVKMRLSVPCRAETCAHLQCFDAVFYLQMNEKK
  PTWMCPVCDKPAPYDQLIIDGLLSKILSECEDADEIEYLVDGSWCPIRAEKERSCSPQGA
  ILVLGPSDANGLLPAPSVNGSGALGSTGGGGPVGSMENGKPGADVVDLTLDSSSSSEDEE
  EEEEEEEDEDEEGPRPKRRCPFQKGLVPAC
• 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. Mediates sumoylation of CEBPA, PARK7, HERC2, MYB, TCF4 and RNF168. Plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway, the p53/TP53 pathway, the Wnt pathway and the steroid hormone signaling pathway. Involved in gene silencing. In Wnt signaling, represses LEF1 and enhances TCF4 transcriptional activities through promoting their sumoylations. Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation. Binds to AT-rich DNA sequences, known as matrix or scaffold attachment regions (MARs/SARs). Catalyzes conjugation of SUMO2 to KAT5 in response to DNA damage, facilitating repair of DNA double-strand breaks (DSBs) via homologous recombination (HR). Mediates sumoylation of PARP1 in response to PARP1 trapping to chromatin.
• Tissue Specificity: Highly expressed in testis and, at lower levels, in spleen, prostate, ovary, colon and peripheral blood leukocytes.
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  Ubiquitin mediated proteolysis (hsa04120)
  JAK-STAT sig.ling pathway (hsa04630)
  Fluid shear stress and atherosclerosis (hsa05418)
• Reactome Pathway:
  SUMOylation of DNA damage response and repair proteins (R-HSA-3108214)
  SUMOylation of transcription factors (R-HSA-3232118)
  SUMOylation of ubiquitinylation proteins (R-HSA-3232142)
  SUMOylation of transcription cofactors (R-HSA-3899300)
  SUMOylation of SUMOylation proteins (R-HSA-4085377)
  SUMOylation of intracellular receptors (R-HSA-4090294)
  SUMOylation of DNA replication proteins (R-HSA-4615885)
  SUMOylation of immune response proteins (R-HSA-4755510)
  Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks (R-HSA-5693565)
  Nonhomologous End-Joining (NHEJ) (R-HSA-5693571)
  Processing of DNA double-strand break ends (R-HSA-5693607)
  G2/M DNA damage checkpoint (R-HSA-69473)
  Vitamin D (calciferol) metabolism (R-HSA-196791)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Colon cancer	DISVC52G	Strong	Altered Expression	[2]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[2]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[3]
Leukemia	DISNAKFL	Strong	Biomarker	[4]
Lung cancer	DISCM4YA	Strong	Biomarker	[5]
Lung carcinoma	DISTR26C	Strong	Biomarker	[5]
Myelodysplastic syndrome	DISYHNUI	Strong	Altered Expression	[6]
Neoplasm	DISZKGEW	Strong	Biomarker	[7]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]
Pancreatic cancer	DISJC981	Strong	Biomarker	[8]
Psoriasis	DIS59VMN	Strong	Genetic Variation	[9]
Retinoblastoma	DISVPNPB	Strong	Biomarker	[10]
Synovial sarcoma	DISEZJS7	Strong	Altered Expression	[11]
Von hippel-lindau disease	DIS6ZFQQ	Strong	Biomarker	[12]
Isolated congenital microcephaly	DISUXHZ6	moderate	Biomarker	[13]
Melanoma	DIS1RRCY	moderate	Altered Expression	[14]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Biomarker	[15]
Nervous system inflammation	DISB3X5A	Limited	Genetic Variation	[16]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[17]
Wilms tumor	DISB6T16	Limited	Biomarker	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of E3 SUMO-protein ligase PIAS4 (PIAS4).	[18]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of E3 SUMO-protein ligase PIAS4 (PIAS4).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 SUMO-protein ligase PIAS4 (PIAS4).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of E3 SUMO-protein ligase PIAS4 (PIAS4).	[20]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of E3 SUMO-protein ligase PIAS4 (PIAS4).	[21]

References

• [1] PIASy mediates hypoxia-induced SIRT1 transcriptional repression and epithelial-to-mesenchymal transition in ovarian cancer cells.J Cell Sci. 2013 Sep 1;126(Pt 17):3939-47. doi: 10.1242/jcs.127381. Epub 2013 Jul 10.
• [2] PIASy stimulates HIF1 SUMOylation and negatively regulates HIF1 activity in response to hypoxia.Oncogene. 2010 Oct 14;29(41):5568-78. doi: 10.1038/onc.2010.297. Epub 2010 Jul 26.
• [3] SUMO E3 Ligase PIASy Mediates High Glucose-Induced Activation of NF-B Inflammatory Signaling in Rat Mesangial Cells.Mediators Inflamm. 2017;2017:1685194. doi: 10.1155/2017/1685194. Epub 2017 Sep 5.
• [4] Interactions between coilin and PIASy partially link Cajal bodies to PML bodies.J Cell Sci. 2005 Nov 1;118(Pt 21):4995-5003. doi: 10.1242/jcs.02613. Epub 2005 Oct 11.
• [5] Hypoxia-induced Slug SUMOylation enhances lung cancer metastasis.J Exp Clin Cancer Res. 2019 Jan 6;38(1):5. doi: 10.1186/s13046-018-0996-8.
• [6] DNA microarray analysis of stage progression mechanism in myelodysplastic syndrome.Br J Haematol. 2003 Oct;123(2):288-96. doi: 10.1046/j.1365-2141.2003.04601.x.
• [7] ROS-PIAS cross talk channelizes ATM signaling from resistance to apoptosis during chemosensitization of resistant tumors.Cell Death Dis. 2014 Jan 23;5(1):e1021. doi: 10.1038/cddis.2013.534.
• [8] PIAS4 is an activator of hypoxia signalling via VHL suppression during growth of pancreatic cancer cells.Br J Cancer. 2013 Oct 1;109(7):1795-804. doi: 10.1038/bjc.2013.531. Epub 2013 Sep 3.
• [9] Regulation of the psoriatic chemokine CCL20 by E3 ligases Trim32 and Piasy in keratinocytes.J Invest Dermatol. 2010 May;130(5):1384-90. doi: 10.1038/jid.2009.416. Epub 2010 Jan 7.
• [10] The E3 SUMO ligase PIASy is a regulator of cellular senescence and apoptosis.Mol Cell. 2006 Jun 23;22(6):783-794. doi: 10.1016/j.molcel.2006.05.016.
• [11] SYT-SSX1 (synovial sarcoma translocated) regulates PIASy ligase activity to cause overexpression of NCOA3 protein.J Biol Chem. 2011 May 27;286(21):18623-32. doi: 10.1074/jbc.M110.176693. Epub 2011 Mar 24.
• [12] Hypoxia inactivates the VHL tumor suppressor through PIASy-mediated SUMO modification.PLoS One. 2010 Mar 16;5(3):e9720. doi: 10.1371/journal.pone.0009720.
• [13] PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome.Eur J Hum Genet. 2015 Dec;23(12):1615-26. doi: 10.1038/ejhg.2015.51. Epub 2015 Apr 8.
• [14] Impaired PIASy-Tip60 signaling weakens activation of p53 in melanoma.Melanoma Res. 2013 Jun;23(3):213-7. doi: 10.1097/CMR.0b013e328361056d.
• [15] Array CGH Analysis of Paired Blood and Tumor Samples from Patients with Sporadic Wilms Tumor.PLoS One. 2015 Aug 28;10(8):e0136812. doi: 10.1371/journal.pone.0136812. eCollection 2015.
• [16] Sumoylation of RORt regulates T(H)17 differentiation and thymocyte development.Nat Commun. 2018 Nov 19;9(1):4870. doi: 10.1038/s41467-018-07203-z.
• [17] The E3 SUMO ligase PIAS is a novel interaction partner regulating the activity of diabetes associated hepatocyte nuclear factor-1.Sci Rep. 2018 Aug 24;8(1):12780. doi: 10.1038/s41598-018-29448-w.
• [18] 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.
• [19] 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.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [22] 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.