Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTR6G4II)

• DOT Name: Cleavage stimulation factor subunit 2 (CSTF2)
• Synonyms: CF-1 64 kDa subunit; Cleavage stimulation factor 64 kDa subunit; CSTF 64 kDa subunit; CstF-64
• Gene Name: CSTF2
• Related Disease:
  Advanced cancer
  Bladder cancer
  Lung cancer
  Lung carcinoma
  Multiple sclerosis
  Non-small-cell lung cancer
  Transitional cell carcinoma
  Urothelial carcinoma
  Enterovirus infection
• UniProt ID: CSTF2_HUMAN
• PDB ID: 1P1T; 2J8P; 6Q2I; 6TZE
• Pfam ID: PF14327 ; PF14304 ; PF00076
• Sequence:
  MAGLTVRDPAVDRSLRSVFVGNIPYEATEEQLKDIFSEVGPVVSFRLVYDRETGKPKGYG
  FCEYQDQETALSAMRNLNGREFSGRALRVDNAASEKNKEELKSLGTGAPVIESPYGETIS
  PEDAPESISKAVASLPPEQMFELMKQMKLCVQNSPQEARNMLLQNPQLAYALLQAQVVMR
  IVDPEIALKILHRQTNIPTLIAGNPQPVHGAGPGSGSNVSMNQQNPQAPQAQSLGGMHVN
  GAPPLMQASMQGGVPAPGQMPAAVTGPGPGSLAPGGGMQAQVGMPGSGPVSMERGQVPMQ
  DPRAAMQRGSLPANVPTPRGLLGDAPNDPRGGTLLSVTGEVEPRGYLGPPHQGPPMHHVP
  GHESRGPPPHELRGGPLPEPRPLMAEPRGPMLDQRGPPLDGRGGRDPRGIDARGMEARAM
  EARGLDARGLEARAMEARAMEARAMEARAMEARAMEVRGMEARGMDTRGPVPGPRGPIPS
  GMQGPSPINMGAVVPQGSRQVPVMQGTGMQGASIQGGSQPGGFSPGQNQVTPQDHEKAAL
  IMQVLQLTADQIAMLPPEQRQSILILKEQIQKSTGAP
• Function: One of the multiple factors required for polyadenylation and 3'-end cleavage of mammalian pre-mRNAs. This subunit is directly involved in the binding to pre-mRNAs.
• KEGG Pathway: mR. surveillance pathway (hsa03015)
• Reactome Pathway:
  mRNA 3'-end processing (R-HSA-72187)
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Processing of Intronless Pre-mRNAs (R-HSA-77595)
  tRNA processing in the nucleus (R-HSA-6784531)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Lung cancer	DISCM4YA	Strong	Altered Expression	[3]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[3]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[1]
Transitional cell carcinoma	DISWVVDR	Strong	Biomarker	[2]
Urothelial carcinoma	DISRTNTN	Strong	Biomarker	[2]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[5]

5 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 Cleavage stimulation factor subunit 2 (CSTF2).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic increases the methylation of Cleavage stimulation factor subunit 2 (CSTF2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cleavage stimulation factor subunit 2 (CSTF2).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Cleavage stimulation factor subunit 2 (CSTF2).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Cleavage stimulation factor subunit 2 (CSTF2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[7]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[13]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[14]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[16]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[16]
Clozapine	DMFC71L	Approved	Clozapine decreases the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[17]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[17]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Cleavage stimulation factor subunit 2 (CSTF2).	[22]

References

• [1] Genome-wide profiling reveals alternative polyadenylation of mRNA in human non-small cell lung cancer.J Transl Med. 2019 Aug 7;17(1):257. doi: 10.1186/s12967-019-1986-0.
• [2] CSTF2-Induced Shortening of the RAC1 3'UTR Promotes the Pathogenesis of Urothelial Carcinoma of the Bladder.Cancer Res. 2018 Oct 15;78(20):5848-5862. doi: 10.1158/0008-5472.CAN-18-0822. Epub 2018 Aug 24.
• [3] Characterization of a cleavage stimulation factor, 3' pre-RNA, subunit 2, 64 kDa (CSTF2) as a therapeutic target for lung cancer.Clin Cancer Res. 2011 Sep 15;17(18):5889-900. doi: 10.1158/1078-0432.CCR-11-0240. Epub 2011 Aug 3.
• [4] A Novel Regulatory Function of Long Non-coding RNAs at Different Levels of Gene Expression in Multiple Sclerosis.J Mol Neurosci. 2019 Mar;67(3):434-440. doi: 10.1007/s12031-018-1248-2. Epub 2019 Jan 4.
• [5] Enterovirus 71 3C protease cleaves a novel target CstF-64 and inhibits cellular polyadenylation.PLoS Pathog. 2009 Sep;5(9):e1000593. doi: 10.1371/journal.ppat.1000593. Epub 2009 Sep 25.
• [6] 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.
• [7] 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.
• [8] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Epigenetic changes in individuals with arsenicosis. Chem Res Toxicol. 2011 Feb 18;24(2):165-7. doi: 10.1021/tx1004419. Epub 2011 Feb 4.
• [13] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [14] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [15] 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.
• [16] 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.
• [17] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [18] 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.
• [19] 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.
• [20] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [21] 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.
• [22] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.