Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVABJ4Z)

• DOT Name: THO complex subunit 1 (THOC1)
• Synonyms: Tho1; Nuclear matrix protein p84; p84N5; hTREX84
• Gene Name: THOC1
• Related Disease:
  Delirium
  Prostate cancer
  Prostate carcinoma
  Schizophrenia
  Breast neoplasm
  Colorectal carcinoma
  Lung neoplasm
  Myopia
  Neoplasm
  Pancreatic adenocarcinoma
  Lung cancer
  Lung carcinoma
  Retinoblastoma
  Adenocarcinoma
  Breast cancer
  Breast carcinoma
  Ductal breast carcinoma in situ
  Epithelial ovarian cancer
  Ovarian cancer
  Ovarian neoplasm
  Pachyonychia congenita 3
  Sensorineural hearing loss disorder
• UniProt ID: THOC1_HUMAN
• PDB ID: 1WXP; 7APK; 7ZNK; 7ZNL
• Pfam ID: PF00531 ; PF11957
• Sequence:
  MSPTPPLFSLPEARTRFTKSTREALNNKNIKPLLSTFSQVPGSENEKKCTLDQAFRGILE
  EEIINHSSCENVLAIISLAIGGVTEGICTASTPFVLLGDVLDCLPLDQCDTIFTFVEKNV
  ATWKSNTFYSAGKNYLLRMCNDLLRRLSKSQNTVFCGRIQLFLARLFPLSEKSGLNLQSQ
  FNLENVTVFNTNEQESTLGQKHTEDREEGMDVEEGEMGDEEAPTTCSIPIDYNLYRKFWS
  LQDYFRNPVQCYEKISWKTFLKYSEEVLAVFKSYKLDDTQASRKKMEELKTGGEHVYFAK
  FLTSEKLMDLQLSDSNFRRHILLQYLILFQYLKGQVKFKSSNYVLTDEQSLWIEDTTKSV
  YQLLSENPPDGERFSKMVEHILNTEENWNSWKNEGCPSFVKERTSDTKPTRIIRKRTAPE
  DFLGKGPTKKILMGNEELTRLWNLCPDNMEACKSETREHMPTLEEFFEEAIEQADPENMV
  ENEYKAVNNSNYGWRALRLLARRSPHFFQPTNQQFKSLPEYLENMVIKLAKELPPPSEEI
  KTGEDEDEEDNDALLKENESPDVRRDKPVTGEQIEVFANKLGEQWKILAPYLEMKDSEIR
  QIECDSEDMKMRAKQLLVAWQDQEGVHATPENLINALNKSGLSDLAESLTNDNETNS
• Function: Required for efficient export of polyadenylated RNA. Acts as component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5' end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NFX1 pathway. The TREX complex is essential for the export of Kaposi's sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production. Regulates transcriptional elongation of a subset of genes. Involved in genome stability by preventing co-transcriptional R-loop formation. May play a role in hair cell formation, hence may be involved in hearing; Participates in an apoptotic pathway which is characterized by activation of caspase-6, increases in the expression of BAK1 and BCL2L1 and activation of NF-kappa-B. This pathway does not require p53/TP53, nor does the presence of p53/TP53 affect the efficiency of cell killing. Activates a G2/M cell cycle checkpoint prior to the onset of apoptosis. Apoptosis is inhibited by association with RB1.
• Tissue Specificity: Ubiquitous. Expressed in various cancer cell lines. Expressed at very low levels in normal breast epithelial cells and highly expressed in breast tumors. Expression is strongly associated with an aggressive phenotype of breast tumors and expression correlates with tumor size and the metastatic state of the tumor progression.
• KEGG Pathway:
  Nucleocytoplasmic transport (hsa03013)
  Spliceosome (hsa03040)
• Reactome Pathway:
  mRNA 3'-end processing (R-HSA-72187)
  RNA Polymerase II Transcription Termination (R-HSA-73856)
  Transport of Mature mRNA derived from an Intron-Containing Transcript (R-HSA-159236)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Delirium	DIS2OKP1	Definitive	Genetic Variation	[1]
Prostate cancer	DISF190Y	Definitive	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[2]
Schizophrenia	DISSRV2N	Definitive	Genetic Variation	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[4]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[5]
Myopia	DISK5S60	Strong	Genetic Variation	[6]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	moderate	Biomarker	[8]
Lung carcinoma	DISTR26C	moderate	Biomarker	[8]
Retinoblastoma	DISVPNPB	moderate	Biomarker	[8]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[9]
Breast cancer	DIS7DPX1	Limited	Biomarker	[10]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[10]
Ductal breast carcinoma in situ	DISLCJY7	Limited	Altered Expression	[11]
Epithelial ovarian cancer	DIS56MH2	Limited	Altered Expression	[12]
Ovarian cancer	DISZJHAP	Limited	Altered Expression	[12]
Ovarian neoplasm	DISEAFTY	Limited	Altered Expression	[12]
Pachyonychia congenita 3	DISZLC6C	Limited	Altered Expression	[13]
Sensorineural hearing loss disorder	DISJV45Z	Limited	Autosomal dominant	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of THO complex subunit 1 (THOC1).	[15]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of THO complex subunit 1 (THOC1).	[16]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of THO complex subunit 1 (THOC1).	[17]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of THO complex subunit 1 (THOC1).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of THO complex subunit 1 (THOC1).	[19]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of THO complex subunit 1 (THOC1).	[19]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil decreases the expression of THO complex subunit 1 (THOC1).	[20]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of THO complex subunit 1 (THOC1).	[21]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of THO complex subunit 1 (THOC1).	[22]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of THO complex subunit 1 (THOC1).	[25]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of THO complex subunit 1 (THOC1).	[26]

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 THO complex subunit 1 (THOC1).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of THO complex subunit 1 (THOC1).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of THO complex subunit 1 (THOC1).	[24]

References

• [1] Short tandem repeat (STR) replacements in UTRs and introns suggest an important role for certain STRs in gene expression and disease.Gene. 2005 Jan 3;344:203-11. doi: 10.1016/j.gene.2004.09.034. Epub 2004 Dec 7.
• [2] VDR regulation of microRNA differs across prostate cell models suggesting extremely flexible control of transcription.Epigenetics. 2015;10(1):40-9. doi: 10.4161/15592294.2014.989088. Epub 2015 Jan 29.
• [3] Linking transcriptional elongation and messenger RNA export to metastatic breast cancers.Cancer Res. 2005 Apr 15;65(8):3011-6. doi: 10.1158/0008-5472.CAN-04-3624.
• [4] Elevated expression of Thoc1 is associated with aggressive phenotype and poor prognosis in colorectal cancer.Biochem Biophys Res Commun. 2015 Dec 4-11;468(1-2):53-8. doi: 10.1016/j.bbrc.2015.10.166. Epub 2015 Nov 3.
• [5] Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers.BMC Cancer. 2011 Feb 17;11:77. doi: 10.1186/1471-2407-11-77.
• [6] Adenomatous Polyposis Coli Mutation Leads to Myopia Development in Mice.PLoS One. 2015 Oct 23;10(10):e0141144. doi: 10.1371/journal.pone.0141144. eCollection 2015.
• [7] Combination gene therapy with p53 and Thoc1/p84 is more effective than either single agent in an animal model of human pancreatic adenocarcinoma.Int J Oncol. 2006 Mar;28(3):781-5.
• [8] Thoc1 inhibits cell growth via induction of cell cycle arrest and apoptosis in lung cancer cells.Mol Med Rep. 2014 Jun;9(6):2321-7. doi: 10.3892/mmr.2014.2088. Epub 2014 Mar 28.
• [9] In vivo and in vitro degradation of heparan sulfate (HS) proteoglycans by HPR1 in pancreatic adenocarcinomas. Loss of cell surface HS suppresses fibroblast growth factor 2-mediated cell signaling and proliferation.J Biol Chem. 2007 Jan 26;282(4):2363-73. doi: 10.1074/jbc.M604218200. Epub 2006 Nov 22.
• [10] 4-HPR Is an Endoplasmic Reticulum Stress Aggravator and Sensitizes Breast Cancer Cells Resistant to TRAIL/Apo2L.Anticancer Res. 2018 Aug;38(8):4403-4416. doi: 10.21873/anticanres.12742.
• [11] Ductal carcinoma in situ of the breast and heparanase-1 expression: a molecular explanation for more aggressive subtypes.J Am Coll Surg. 2005 Mar;200(3):328-35. doi: 10.1016/j.jamcollsurg.2004.10.034.
• [12] Transcriptional regulation of hTREX84 in human cancer cells.PLoS One. 2012;7(8):e43610. doi: 10.1371/journal.pone.0043610. Epub 2012 Aug 27.
• [13] Profiling of zinc-altered gene expression in human prostate normal vs. cancer cells: a time course study.J Nutr Biochem. 2009 Dec;20(12):1000-12. doi: 10.1016/j.jnutbio.2008.09.004. Epub 2008 Dec 13.
• [14] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [15] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [16] 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.
• [17] 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.
• [18] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [19] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [20] Cellular response to 5-fluorouracil (5-FU) in 5-FU-resistant colon cancer cell lines during treatment and recovery. Mol Cancer. 2006 May 18;5:20. doi: 10.1186/1476-4598-5-20.
• [21] Nicotinic modulation of gene expression in SH-SY5Y neuroblastoma cells. Brain Res. 2006 Oct 20;1116(1):39-49.
• [22] Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro. Cell Biol Toxicol. 2023 Feb;39(1):319-343. doi: 10.1007/s10565-022-09730-4. Epub 2022 Jun 15.
• [23] 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.
• [24] 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.
• [25] Bisphenol A Exposure Changes the Transcriptomic and Proteomic Dynamics of Human Retinoblastoma Y79 Cells. Genes (Basel). 2021 Feb 11;12(2):264. doi: 10.3390/genes12020264.
• [26] Transcriptome dynamics of alternative splicing events revealed early phase of apoptosis induced by methylparaben in H1299 human lung carcinoma cells. Arch Toxicol. 2020 Jan;94(1):127-140. doi: 10.1007/s00204-019-02629-w. Epub 2019 Nov 20.