Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKXQD70)

• DOT Name: Protein argonaute-4 (AGO4)
• Synonyms: Argonaute4; hAgo4; Argonaute RISC catalytic component 4; Eukaryotic translation initiation factor 2C 4; eIF-2C 4; eIF2C 4
• Gene Name: AGO4
• Related Disease:
  Breast cancer
  Breast carcinoma
  Breast neoplasm
• UniProt ID: AGO4_HUMAN
• PDB ID: 6OON
• Pfam ID: PF08699 ; PF16488 ; PF16487 ; PF16486 ; PF02170 ; PF02171
• Sequence:
  MEALGPGPPASLFQPPRRPGLGTVGKPIRLLANHFQVQIPKIDVYHYDVDIKPEKRPRRV
  NREVVDTMVRHFKMQIFGDRQPGYDGKRNMYTAHPLPIGRDRVDMEVTLPGEGKDQTFKV
  SVQWVSVVSLQLLLEALAGHLNEVPDDSVQALDVITRHLPSMRYTPVGRSFFSPPEGYYH
  PLGGGREVWFGFHQSVRPAMWNMMLNIDVSATAFYRAQPIIEFMCEVLDIQNINEQTKPL
  TDSQRVKFTKEIRGLKVEVTHCGQMKRKYRVCNVTRRPASHQTFPLQLENGQAMECTVAQ
  YFKQKYSLQLKYPHLPCLQVGQEQKHTYLPLEVCNIVAGQRCIKKLTDNQTSTMIKATAR
  SAPDRQEEISRLVKSNSMVGGPDPYLKEFGIVVHNEMTELTGRVLPAPMLQYGGRNKTVA
  TPNQGVWDMRGKQFYAGIEIKVWAVACFAPQKQCREDLLKSFTDQLRKISKDAGMPIQGQ
  PCFCKYAQGADSVEPMFKHLKMTYVGLQLIVVILPGKTPVYAEVKRVGDTLLGMATQCVQ
  VKNVVKTSPQTLSNLCLKINAKLGGINNVLVPHQRPSVFQQPVIFLGADVTHPPAGDGKK
  PSIAAVVGSMDGHPSRYCATVRVQTSRQEISQELLYSQEVIQDLTNMVRELLIQFYKSTR
  FKPTRIIYYRGGVSEGQMKQVAWPELIAIRKACISLEEDYRPGITYIVVQKRHHTRLFCA
  DKTERVGKSGNVPAGTTVDSTITHPSEFDFYLCSHAGIQGTSRPSHYQVLWDDNCFTADE
  LQLLTYQLCHTYVRCTRSVSIPAPAYYARLVAFRARYHLVDKDHDSAEGSHVSGQSNGRD
  PQALAKAVQIHHDTQHTMYFA
• Function: Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) and represses the translation of mRNAs which are complementary to them. Lacks endonuclease activity and does not appear to cleave target mRNAs. Also required for RNA-directed transcription and replication of the human hapatitis delta virus (HDV).
• Reactome Pathway:
  MicroRNA (miRNA) biogenesis (R-HSA-203927)
  Oxidative Stress Induced Senescence (R-HSA-2559580)
  Oncogene Induced Senescence (R-HSA-2559585)
  Ca2+ pathway (R-HSA-4086398)
  Small interfering RNA (siRNA) biogenesis (R-HSA-426486)
  Post-transcriptional silencing by small RNAs (R-HSA-426496)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  MAPK6/MAPK4 signaling (R-HSA-5687128)
  Transcriptional Regulation by VENTX (R-HSA-8853884)
  Regulation of RUNX1 Expression and Activity (R-HSA-8934593)
  RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function (R-HSA-8936459)
  Regulation of PTEN mRNA translation (R-HSA-8943723)
  Competing endogenous RNAs (ceRNAs) regulate PTEN translation (R-HSA-8948700)
  Transcriptional Regulation by MECP2 (R-HSA-8986944)
  Estrogen-dependent gene expression (R-HSA-9018519)
  Regulation of MECP2 expression and activity (R-HSA-9022692)
  NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux (R-HSA-9029569)
  Regulation of CDH11 mRNA translation by microRNAs (R-HSA-9759811)
  Regulation of NPAS4 mRNA translation (R-HSA-9768778)
  Pre-NOTCH Transcription and Translation (R-HSA-1912408)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]

10 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 Protein argonaute-4 (AGO4).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein argonaute-4 (AGO4).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Protein argonaute-4 (AGO4).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Protein argonaute-4 (AGO4).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein argonaute-4 (AGO4).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein argonaute-4 (AGO4).	[7]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Protein argonaute-4 (AGO4).	[8]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Protein argonaute-4 (AGO4).	[9]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Protein argonaute-4 (AGO4).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Protein argonaute-4 (AGO4).	[10]

1 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 increases the methylation of Protein argonaute-4 (AGO4).	[11]

References

• [1] Argonaute-2 expression is regulated by epidermal growth factor receptor and mitogen-activated protein kinase signaling and correlates with a transformed phenotype in breast cancer cells.Endocrinology. 2009 Jan;150(1):14-23. doi: 10.1210/en.2008-0984. Epub 2008 Sep 11.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] 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.
• [5] 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.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [8] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [9] Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] 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.