Details of Drug Off-Target (DOT)

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

• DOT Name: Sentrin-specific protease 3 (SENP3)
• Synonyms: EC 3.4.22.-; SUMO-1-specific protease 3; Sentrin/SUMO-specific protease SENP3
• Gene Name: SENP3
• Related Disease:
  Advanced cancer
  Epithelial ovarian cancer
  Gastric cancer
  Stomach cancer
  Coronary atherosclerosis
  Myocardial ischemia
  Neoplasm
  Squamous cell carcinoma
  Colon adenocarcinoma
  Progressive multifocal leukoencephalopathy
  Promyelocytic leukaemia
• UniProt ID: SENP3_HUMAN
• EC Number: 3.4.22.-
• Pfam ID: PF02902 ; PF19722
• Sequence:
  MKETIQGTGSWGPEPPGPGIPPAYSSPRRERLRWPPPPKPRLKSGGGFGPDPGSGTTVPA
  RRLPVPRPSFDASASEEEEEEEEEEDEDEEEEVAAWRLPPRWSQLGTSQRPRPSRPTHRK
  TCSQRRRRAMRAFRMLLYSKSTSLTFHWKLWGRHRGRRRGLAHPKNHLSPQQGGATPQVP
  SPCCRFDSPRGPPPPRLGLLGALMAEDGVRGSPPVPSGPPMEEDGLRWTPKSPLDPDSGL
  LSCTLPNGFGGQSGPEGERSLAPPDASILISNVCSIGDHVAQELFQGSDLGMAEEAERPG
  EKAGQHSPLREEHVTCVQSILDEFLQTYGSLIPLSTDEVVEKLEDIFQQEFSTPSRKGLV
  LQLIQSYQRMPGNAMVRGFRVAYKRHVLTMDDLGTLYGQNWLNDQVMNMYGDLVMDTVPE
  KVHFFNSFFYDKLRTKGYDGVKRWTKNVDIFNKELLLIPIHLEVHWSLISVDVRRRTITY
  FDSQRTLNRRCPKHIAKYLQAEAVKKDRLDFHQGWKGYFKMNVARQNNDSDCGAFVLQYC
  KHLALSQPFSFTQQDMPKLRRQIYKELCHCKLTV
• Function: Protease that releases SUMO2 and SUMO3 monomers from sumoylated substrates, but has only weak activity against SUMO1 conjugates. Deconjugates SUMO2 from MEF2D, which increases its transcriptional activation capability. Deconjugates SUMO2 and SUMO3 from CDCA8. Redox sensor that, when redistributed into nucleoplasm, can act as an effector to enhance HIF1A transcriptional activity by desumoylating EP300. Required for rRNA processing through deconjugation of SUMO2 and SUMO3 from nucleophosmin, NPM1. Plays a role in the regulation of sumoylation status of ZNF148. Functions as a component of the Five Friends of Methylated CHTOP (5FMC) complex; the 5FMC complex is recruited to ZNF148 by methylated CHTOP, leading to desumoylation of ZNF148 and subsequent transactivation of ZNF148 target genes. Deconjugates SUMO2 from KAT5.
• Reactome Pathway: Major pathway of rRNA processing in the nucleolus and cytosol (R-HSA-6791226)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[3]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[3]
Coronary atherosclerosis	DISKNDYU	moderate	Biomarker	[4]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[4]
Neoplasm	DISZKGEW	moderate	Biomarker	[5]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[5]
Colon adenocarcinoma	DISDRE0J	Limited	Biomarker	[6]
Progressive multifocal leukoencephalopathy	DISX02WS	Limited	Biomarker	[6]
Promyelocytic leukaemia	DISYGG13	Limited	Biomarker	[6]

7 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 Sentrin-specific protease 3 (SENP3).	[7]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sentrin-specific protease 3 (SENP3).	[8]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Sentrin-specific protease 3 (SENP3).	[10]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Sentrin-specific protease 3 (SENP3).	[11]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Sentrin-specific protease 3 (SENP3).	[12]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Sentrin-specific protease 3 (SENP3).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Sentrin-specific protease 3 (SENP3).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Sentrin-specific protease 3 (SENP3).	[9]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Sentrin-specific protease 3 (SENP3).	[9]

References

• [1] Mitotic Phosphorylation of SENP3 Regulates DeSUMOylation of Chromosome-Associated Proteins and Chromosome Stability.Cancer Res. 2018 May 1;78(9):2171-2178. doi: 10.1158/0008-5472.CAN-17-2288. Epub 2018 Feb 8.
• [2] Upregulation of SENP3/SMT3IP1 promotes epithelial ovarian cancer progression and forecasts poor prognosis.Tumour Biol. 2017 Mar;39(3):1010428317694543. doi: 10.1177/1010428317694543.
• [3] De-SUMOylation of FOXC2 by SENP3 promotes the epithelial-mesenchymal transition in gastric cancer cells.Oncotarget. 2014 Aug 30;5(16):7093-104. doi: 10.18632/oncotarget.2197.
• [4] The desumoylating enzyme sentrin-specific protease 3 contributes to myocardial ischemia reperfusion injury.J Genet Genomics. 2018 Mar 20;45(3):125-135. doi: 10.1016/j.jgg.2017.12.002. Epub 2017 Dec 29.
• [5] Overexpression of SENP3 in oral squamous cell carcinoma and its association with differentiation.Oncol Rep. 2013 May;29(5):1701-6. doi: 10.3892/or.2013.2318. Epub 2013 Mar 1.
• [6] SENP3-mediated de-conjugation of SUMO2/3 from promyelocytic leukemia is correlated with accelerated cell proliferation under mild oxidative stress.J Biol Chem. 2010 Apr 23;285(17):12906-15. doi: 10.1074/jbc.M109.071431. Epub 2010 Feb 24.
• [7] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [8] 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.
• [9] 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.
• [10] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [13] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [14] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.