Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT655XF8)

• DOT Name: Polycomb protein SUZ12 (SUZ12)
• Synonyms: Chromatin precipitated E2F target 9 protein; ChET 9 protein; Joined to JAZF1 protein; Suppressor of zeste 12 protein homolog
• Gene Name: SUZ12
• Related Disease:
  Breast cancer
  Breast carcinoma
  Glioma
  Imagawa-Matsumoto syndrome
  Neurofibromatosis
  Advanced cancer
  Breast neoplasm
  Carcinoma
  Cervical cancer
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Endometrial carcinoma
  Epithelial ovarian cancer
  Hepatitis B virus infection
  Hepatocellular carcinoma
  Malignant peripheral nerve sheath tumor
  Neurofibromatosis type 1
  T-cell acute lymphoblastic leukaemia
  Urinary bladder neoplasm
  Gastric cancer
  Intellectual disability
  Melanoma
  Metastatic malignant neoplasm
  Squamous cell carcinoma
  Stomach cancer
  Weaver syndrome
  Adenoma
  Adult glioblastoma
  Malignant glioma
  Melanocytic nevus
  Mixed glioma
  Schwannoma
  Acute myelogenous leukaemia
  Carcinoma of liver and intrahepatic biliary tract
  Endometrium neoplasm
  Glioblastoma multiforme
  Liver cancer
  Nerve sheath neoplasm
  Neuroblastoma
  Neurofibroma
  Osteosarcoma
  Plexiform neurofibroma
• UniProt ID: SUZ12_HUMAN
• PDB ID: 4W2R; 5HYN; 5IJ7; 5IJ8; 5LS6; 5WAI; 5WAK; 5WG6; 6B3W; 6C23; 6C24; 6NQ3; 6WKR; 7AT8; 7KSO; 7KSR; 7KTP; 7TD5; 8FYH
• Pfam ID: PF09733
• Sequence:
  MAPQKHGGGGGGGSGPSAGSGGGGFGGSAAVAAATASGGKSGGGSCGGGGSYSASSSSSA
  AAAAGAAVLPVKKPKMEHVQADHELFLQAFEKPTQIYRFLRTRNLIAPIFLHRTLTYMSH
  RNSRTNIKRKTFKVDDMLSKVEKMKGEQESHSLSAHLQLTFTGFFHKNDKPSPNSENEQN
  SVTLEVLLVKVCHKKRKDVSCPIRQVPTGKKQVPLNPDLNQTKPGNFPSLAVSSNEFEPS
  NSHMVKSYSLLFRVTRPGRREFNGMINGETNENIDVNEELPARRKRNREDGEKTFVAQMT
  VFDKNRRLQLLDGEYEVAMQEMEECPISKKRATWETILDGKRLPPFETFSQGPTLQFTLR
  WTGETNDKSTAPIAKPLATRNSESLHQENKPGSVKPTQTIAVKESLTTDLQTRKEKDTPN
  ENRQKLRIFYQFLYNNNTRQQTEARDDLHCPWCTLNCRKLYSLLKHLKLCHSRFIFNYVY
  HPKGARIDVSINECYDGSYAGNPQDIHRQPGFAFSRNGPVKRTPITHILVCRPKRTKASM
  SEFLESEDGEVEQQRTYSSGHNRLYFHSDTCLPLRPQEMEVDSEDEKDPEWLREKTITQI
  EEFSDVNEGEKEVMKLWNLHVMKHGFIADNQMNHACMLFVENYGQKIIKKNLCRNFMLHL
  VSMHDFNLISIMSIDKAVTKLREMQQKLEKGESASPANEEITEEQNGTANGFSEINSKEK
  ALETDSVSGVSKQSKKQKL
• Function: Polycomb group (PcG) protein. Component of the PRC2 complex, which methylates 'Lys-9' (H3K9me) and 'Lys-27' (H3K27me) of histone H3, leading to transcriptional repression of the affected target gene. The PRC2 complex may also serve as a recruiting platform for DNA methyltransferases, thereby linking two epigenetic repression systems. Genes repressed by the PRC2 complex include HOXC8, HOXA9, MYT1 and CDKN2A.
• Tissue Specificity: Overexpressed in breast and colon cancer.
• KEGG Pathway: Polycomb repressive complex (hsa03083)
• Reactome Pathway:
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  PKMTs methylate histone lysines (R-HSA-3214841)
  SUMOylation of chromatin organization proteins (R-HSA-4551638)
  Activation of anterior HOX genes in hindbrain development during early embryogenesis (R-HSA-5617472)
  Regulation of PTEN gene transcription (R-HSA-8943724)
  Transcriptional Regulation by E2F6 (R-HSA-8953750)
  HCMV Early Events (R-HSA-9609690)
  Defective pyroptosis (R-HSA-9710421)
  PRC2 methylates histones and DNA (R-HSA-212300)

Molecular Interaction Atlas (MIA) of This DOT

43 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Biomarker	[1]
Breast carcinoma	DIS2UE88	Definitive	Biomarker	[1]
Glioma	DIS5RPEH	Definitive	Biomarker	[2]
Imagawa-Matsumoto syndrome	DISE13Q9	Definitive	Autosomal dominant	[3]
Neurofibromatosis	DIS5N2R6	Definitive	Biomarker	[4]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Carcinoma	DISH9F1N	Strong	Altered Expression	[7]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[8]
Colon cancer	DISVC52G	Strong	Altered Expression	[9]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[10]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[12]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[13]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[14]
Malignant peripheral nerve sheath tumor	DIS0JTN6	Strong	Genetic Variation	[15]
Neurofibromatosis type 1	DIS53JH9	Strong	Genetic Variation	[16]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Altered Expression	[17]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	moderate	Altered Expression	[18]
Intellectual disability	DISMBNXP	moderate	Biomarker	[19]
Melanoma	DIS1RRCY	moderate	Genetic Variation	[2]
Metastatic malignant neoplasm	DIS86UK6	moderate	Altered Expression	[20]
Squamous cell carcinoma	DISQVIFL	moderate	Biomarker	[21]
Stomach cancer	DISKIJSX	moderate	Altered Expression	[18]
Weaver syndrome	DIS2CE7R	Supportive	Autosomal dominant	[3]
Adenoma	DIS78ZEV	Disputed	Biomarker	[2]
Adult glioblastoma	DISVP4LU	Disputed	Biomarker	[22]
Malignant glioma	DISFXKOV	Disputed	Biomarker	[2]
Melanocytic nevus	DISYS32D	Disputed	Biomarker	[2]
Mixed glioma	DIS64UY3	Disputed	Biomarker	[2]
Schwannoma	DISTTVLA	Disputed	Biomarker	[2]
Acute myelogenous leukaemia	DISCSPTN	Limited	Biomarker	[23]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Limited	Altered Expression	[14]
Endometrium neoplasm	DIS6OS2L	Limited	Biomarker	[11]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[22]
Liver cancer	DISDE4BI	Limited	Altered Expression	[14]
Nerve sheath neoplasm	DISJYLBY	Limited	Biomarker	[24]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[25]
Neurofibroma	DISIJJMH	Limited	Genetic Variation	[26]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[27]
Plexiform neurofibroma	DISW4XX7	Limited	Genetic Variation	[28]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
(+)-JQ1	DM1CZSJ	Phase 1	Polycomb protein SUZ12 (SUZ12) increases the response to substance of (+)-JQ1.	[2]

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 Polycomb protein SUZ12 (SUZ12).	[29]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Polycomb protein SUZ12 (SUZ12).	[30]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Polycomb protein SUZ12 (SUZ12).	[31]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Polycomb protein SUZ12 (SUZ12).	[32]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Polycomb protein SUZ12 (SUZ12).	[33]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Polycomb protein SUZ12 (SUZ12).	[34]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Polycomb protein SUZ12 (SUZ12).	[35]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Polycomb protein SUZ12 (SUZ12).	[36]
Enzalutamide	DMGL19D	Approved	Enzalutamide decreases the expression of Polycomb protein SUZ12 (SUZ12).	[37]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Polycomb protein SUZ12 (SUZ12).	[38]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Polycomb protein SUZ12 (SUZ12).	[35]
GSK2816126	DMJDVW4	Phase 1	GSK2816126 decreases the expression of Polycomb protein SUZ12 (SUZ12).	[37]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Polycomb protein SUZ12 (SUZ12).	[40]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Polycomb protein SUZ12 (SUZ12).	[42]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Polycomb protein SUZ12 (SUZ12).	[43]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Polycomb protein SUZ12 (SUZ12).	[44]

3 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 decreases the sumoylation of Polycomb protein SUZ12 (SUZ12).	[39]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Polycomb protein SUZ12 (SUZ12).	[41]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Polycomb protein SUZ12 (SUZ12).	[41]

References

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• [2] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [3] Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome. Hum Mutat. 2017 Jun;38(6):637-648. doi: 10.1002/humu.23200. Epub 2017 Mar 15.
• [4] Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival.Mod Pathol. 2016 Jun;29(6):582-90. doi: 10.1038/modpathol.2016.45. Epub 2016 Mar 18.
• [5] Activation of EZH2 and SUZ12 Regulated by E2F1 Predicts the Disease Progression and Aggressive Characteristics of Bladder Cancer.Clin Cancer Res. 2015 Dec 1;21(23):5391-403. doi: 10.1158/1078-0432.CCR-14-2680. Epub 2015 Aug 12.
• [6] Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells.Mol Cell. 2010 Sep 10;39(5):761-72. doi: 10.1016/j.molcel.2010.08.013.
• [7] Deregulated expression of the polycomb-group protein SUZ12 target genes characterizes mantle cell lymphoma.Am J Pathol. 2010 Aug;177(2):930-42. doi: 10.2353/ajpath.2010.090769. Epub 2010 Jun 17.
• [8] Bridging Links between Long Noncoding RNA HOTAIR and HPV Oncoprotein E7 in Cervical Cancer Pathogenesis.Sci Rep. 2015 Jul 8;5:11724. doi: 10.1038/srep11724.
• [9] Restoration of IGF2 imprinting by polycomb repressive complex 2 docking factor SUZ12 in colon cancer cells.Exp Cell Res. 2015 Nov 1;338(2):214-21. doi: 10.1016/j.yexcr.2015.09.016. Epub 2015 Sep 25.
• [10] Expression and clinicopathological significance of EED, SUZ12 and EZH2 mRNA in colorectal cancer.J Cancer Res Clin Oncol. 2015 Apr;141(4):661-9. doi: 10.1007/s00432-014-1854-5. Epub 2014 Oct 19.
• [11] Multiple loci identified in a genome-wide association study of prostate cancer.Nat Genet. 2008 Mar;40(3):310-5. doi: 10.1038/ng.91. Epub 2008 Feb 10.
• [12] SUZ12 promotes human epithelial ovarian cancer by suppressing apoptosis via silencing HRK.Mol Cancer Res. 2012 Nov;10(11):1462-72. doi: 10.1158/1541-7786.MCR-12-0335. Epub 2012 Sep 10.
• [13] PLK1 and HOTAIR Accelerate Proteasomal Degradation of SUZ12 and ZNF198 during Hepatitis B Virus-Induced Liver Carcinogenesis.Cancer Res. 2015 Jun 1;75(11):2363-74. doi: 10.1158/0008-5472.CAN-14-2928. Epub 2015 Apr 8.
• [14] The Down-Regulation of SUZ12 Accelerates the Migration and Invasion of Liver Cancer Cells via Activating ERK1/2 Pathway.J Cancer. 2019 Feb 23;10(6):1375-1384. doi: 10.7150/jca.29932. eCollection 2019.
• [15] Low mutation burden and frequent loss of CDKN2A/B and SMARCA2, but not PRC2, define premalignant neurofibromatosis type 1-associated atypical neurofibromas.Neuro Oncol. 2019 Aug 5;21(8):981-992. doi: 10.1093/neuonc/noz028.
• [16] Emerging genotype-phenotype relationships in patients with large NF1 deletions. Hum Genet. 2017 Apr;136(4):349-376. doi: 10.1007/s00439-017-1766-y. Epub 2017 Feb 17.
• [17] Suz12 inactivation cooperates with JAK3 mutant signaling in the development of T-cell acute lymphoblastic leukemia.Blood. 2019 Oct 17;134(16):1323-1336. doi: 10.1182/blood.2019000015.
• [18] Ubiquitin-specific protease 3 promotes cell migration and invasion by interacting with and deubiquitinating SUZ12 in gastric cancer.J Exp Clin Cancer Res. 2019 Jun 24;38(1):277. doi: 10.1186/s13046-019-1270-4.
• [19] PRC2-complex related dysfunction in overgrowth syndromes: A review of EZH2, EED, and SUZ12 and their syndromic phenotypes.Am J Med Genet C Semin Med Genet. 2019 Dec;181(4):519-531. doi: 10.1002/ajmg.c.31754. Epub 2019 Nov 14.
• [20] Pulmonary Metastases Exhibit Epigenetic Clonality: Implications for Precision Cancer Therapy.Ann Thorac Surg. 2015 Nov;100(5):1839-48; discussion 1848. doi: 10.1016/j.athoracsur.2015.05.089. Epub 2015 Aug 20.
• [21] SUZ12 is a novel putative oncogene promoting tumorigenesis in head and neck squamous cell carcinoma.J Cell Mol Med. 2018 Jul;22(7):3582-3594. doi: 10.1111/jcmm.13638. Epub 2018 Apr 18.
• [22] LncRNA TRG-AS1 promotes glioblastoma cell proliferation by competitively binding with miR-877-5p to regulate SUZ12 expression.Pathol Res Pract. 2019 Aug;215(8):152476. doi: 10.1016/j.prp.2019.152476. Epub 2019 May 28.
• [23] Sequential gain of mutations in severe congenital neutropenia progressing to acute myeloid leukemia.Blood. 2012 May 31;119(22):5071-7. doi: 10.1182/blood-2012-01-406116. Epub 2012 Feb 27.
• [24] PRC2 is recurrently inactivated through EED or SUZ12 loss in malignant peripheral nerve sheath tumors.Nat Genet. 2014 Nov;46(11):1227-32. doi: 10.1038/ng.3095. Epub 2014 Sep 21.
• [25] CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2.J Clin Invest. 2018 Jan 2;128(1):446-462. doi: 10.1172/JCI90793. Epub 2017 Dec 4.
• [26] Somatic mutations of SUZ12 in malignant peripheral nerve sheath tumors.Nat Genet. 2014 Nov;46(11):1170-2. doi: 10.1038/ng.3116. Epub 2014 Oct 12.
• [27] Analyzing the disease module associated with osteosarcoma via a network- and pathway-based approach.Exp Ther Med. 2018 Sep;16(3):2584-2592. doi: 10.3892/etm.2018.6506. Epub 2018 Jul 23.
• [28] Non-coding RNA ANRIL and the number of plexiform neurofibromas in patients with NF1 microdeletions.BMC Med Genet. 2012 Oct 26;13:98. doi: 10.1186/1471-2350-13-98.
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• [30] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [31] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [32] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [33] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [34] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [35] 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.
• [36] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [37] Dual targeting of EZH2 and androgen receptor as a novel therapy for castration-resistant prostate cancer. Toxicol Appl Pharmacol. 2020 Oct 1;404:115200. doi: 10.1016/j.taap.2020.115200. Epub 2020 Aug 14.
• [38] Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. 2008 Sep;39(3):312-23. doi: 10.1165/rcmb.2008-0012OC. Epub 2008 Apr 17.
• [39] 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.
• [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] Isobaric tags for relative and absolute quantitation-based proteomics analysis of the effect of ginger oil on bisphenol A-induced breast cancer cell proliferation. Oncol Lett. 2021 Feb;21(2):101. doi: 10.3892/ol.2020.12362. Epub 2020 Dec 8.
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• [44] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [45] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.