Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK7S078)

• DOT Name: Dual specificity protein phosphatase 16 (DUSP16)
• Synonyms: EC 3.1.3.16; EC 3.1.3.48; Mitogen-activated protein kinase phosphatase 7; MAP kinase phosphatase 7; MKP-7
• Gene Name: DUSP16
• Related Disease:
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Burkitt lymphoma
  Liver cancer
  Neoplasm
  Prostate carcinoma
  Hepatocellular carcinoma
  Ulcerative colitis
  Inflammatory bowel disease
• UniProt ID: DUS16_HUMAN
• PDB ID: 2VSW; 3TG3; 4YR8
• EC Number: 3.1.3.16; 3.1.3.48
• Pfam ID: PF00782 ; PF00581
• Sequence:
  MAHEMIGTQIVTERLVALLESGTEKVLLIDSRPFVEYNTSHILEAININCSKLMKRRLQQ
  DKVLITELIQHSAKHKVDIDCSQKVVVYDQSSQDVASLSSDCFLTVLLGKLEKSFNSVHL
  LAGGFAEFSRCFPGLCEGKSTLVPTCISQPCLPVANIGPTRILPNLYLGCQRDVLNKELM
  QQNGIGYVLNASNTCPKPDFIPESHFLRVPVNDSFCEKILPWLDKSVDFIEKAKASNGCV
  LVHCLAGISRSATIAIAYIMKRMDMSLDEAYRFVKEKRPTISPNFNFLGQLLDYEKKIKN
  QTGASGPKSKLKLLHLEKPNEPVPAVSEGGQKSETPLSPPCADSATSEAAGQRPVHPASV
  PSVPSVQPSLLEDSPLVQALSGLHLSADRLEDSNKLKRSFSLDIKSVSYSASMAASLHGF
  SSSEDALEYYKPSTTLDGTNKLCQFSPVQELSEQTPETSPDKEEASIPKKLQTARPSDSQ
  SKRLHSVRTSSSGTAQRSLLSPLHRSGSVEDNYHTSFLFGLSTSQQHLTKSAGLGLKGWH
  SDILAPQTSTPSLTSSWYFATESSHFYSASAIYGGSASYSAYSCSQLPTCGDQVYSVRRR
  QKPSDRADSRRSWHEESPFEKQFKRRSCQMEFGESIMSENRSREELGKVGSQSSFSGSME
  IIEVS
• Function: Dual specificity protein phosphatase involved in the inactivation of MAP kinases. Dephosphorylates MAPK10 bound to ARRB2.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  Efferocytosis (hsa04148)
• Reactome Pathway:
  Negative regulation of MAPK pathway (R-HSA-5675221)
  Suppression of autophagy (R-HSA-9636569)
  Signaling by MAPK mutants (R-HSA-9652817)
  RAF-independent MAPK1/3 activation (R-HSA-112409)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Burkitt lymphoma	DIS9D5XU	Strong	Posttranslational Modification	[1]
Liver cancer	DISDE4BI	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[6]
Ulcerative colitis	DIS8K27O	moderate	Genetic Variation	[7]
Inflammatory bowel disease	DISGN23E	Limited	Genetic Variation	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Dual specificity protein phosphatase 16 (DUSP16).	[9]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Dual specificity protein phosphatase 16 (DUSP16).	[14]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the methylation of Dual specificity protein phosphatase 16 (DUSP16).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Dual specificity protein phosphatase 16 (DUSP16).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Dual specificity protein phosphatase 16 (DUSP16).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Dual specificity protein phosphatase 16 (DUSP16).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[11]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[16]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[18]
Sertraline	DM0FB1J	Approved	Sertraline increases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[16]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[22]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[24]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[26]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Dual specificity protein phosphatase 16 (DUSP16).	[27]

References

• [1] DUSP16 is an epigenetically regulated determinant of JNK signalling in Burkitt's lymphoma.Br J Cancer. 2010 Jul 13;103(2):265-74. doi: 10.1038/sj.bjc.6605711. Epub 2010 Jun 15.
• [2] Reciprocal Regulation of DUSP9 and DUSP16 Expression by HIF1 Controls ERK and p38 MAP Kinase Activity and Mediates Chemotherapy-Induced Breast Cancer Stem Cell Enrichment.Cancer Res. 2018 Aug 1;78(15):4191-4202. doi: 10.1158/0008-5472.CAN-18-0270. Epub 2018 Jun 7.
• [3] DUSP16 ablation arrests the cell cycle and induces cellular senescence.FEBS J. 2015 Dec;282(23):4580-94. doi: 10.1111/febs.13518. Epub 2015 Oct 19.
• [4] MicroRNA-27a-3p inhibits cell viability and migration through down-regulating DUSP16 in hepatocellular carcinoma.J Cell Biochem. 2018 Jul;119(7):5143-5152. doi: 10.1002/jcb.26526. Epub 2018 Apr 17.
• [5] Expression mapping at 12p12-13 in advanced prostate carcinoma.Int J Cancer. 2004 May 1;109(5):668-72. doi: 10.1002/ijc.20060.
• [6] Cks1 regulates human hepatocellular carcinoma cell progression through osteopontin expression.Biochem Biophys Res Commun. 2019 Jan 1;508(1):275-281. doi: 10.1016/j.bbrc.2018.11.070. Epub 2018 Nov 26.
• [7] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [8] Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012 Nov 1;491(7422):119-24. doi: 10.1038/nature11582.
• [9] 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.
• [10] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [11] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [12] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [13] 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.
• [14] Effect of prenatal arsenic exposure on DNA methylation and leukocyte subpopulations in cord blood. Epigenetics. 2014 May;9(5):774-82. doi: 10.4161/epi.28153. Epub 2014 Feb 13.
• [15] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [16] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [17] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [18] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [19] Sertraline induces endoplasmic reticulum stress in hepatic cells. Toxicology. 2014 Aug 1;322:78-88. doi: 10.1016/j.tox.2014.05.007. Epub 2014 May 24.
• [20] 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.
• [21] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [22] 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.
• [23] 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.
• [24] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [25] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [26] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [27] 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.