Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6GDV46)

• DOT Name: Integrator complex subunit 6 (INTS6)
• Synonyms: Int6; DBI-1; Protein DDX26; Protein deleted in cancer 1; DICE1
• Gene Name: INTS6
• Related Disease:
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Breast cancer
  Breast carcinoma
  Colonic neoplasm
  Eclampsia
  Esophageal squamous cell carcinoma
  Hepatocellular carcinoma
  Lung neoplasm
  Neuroblastoma
  Precancerous condition
  Nasopharyngeal carcinoma
  Breast neoplasm
  Carcinoma
  Castration-resistant prostate carcinoma
  Colorectal adenoma
  Non-small-cell lung cancer
  Retinoblastoma
• UniProt ID: INT6_HUMAN
• PDB ID: 7BV7; 7CUN; 7PKS; 7YCX
• Pfam ID: PF15300 ; PF13519
• Sequence:
  MPILLFLIDTSASMNQRSHLGTTYLDTAKGAVETFMKLRARDPASRGDRYMLVTFEEPPY
  AIKAGWKENHATFMNELKNLQAEGLTTLGQSLRTAFDLLNLNRLVTGIDNYGQGRNPFFL
  EPAIIITITDGSKLTTTSGVQDELHLPLNSPLPGSELTKEPFRWDQRLFALVLRLPGTMS
  VESEQLTGVPLDDSAITPMCEVTGGRSYSVCSPRMLNQCLESLVQKVQSGVVINFEKAGP
  DPSPVEDGQPDISRPFGSQPWHSCHKLIYVRPNPKTGVPIGHWPVPESFWPDQNSPTLPP
  RTSHPVVKFSCTDCEPMVIDKLPFDKYELEPSPLTQFILERKSPQTCWQVYVSNSAKYSE
  LGHPFGYLKASTALNCVNLFVMPYNYPVLLPLLDDLFKVHKAKPTLKWRQSFESYLKTMP
  PYYLGPLKKAVRMMGAPNLIADSMEYGLSYSVISYLKKLSQQAKIESDRVIGSVGKKVVQ
  ETGIKVRSRSHGLSMAYRKDFQQLLQGISEDVPHRLLDLNMKEYTGFQVALLNKDLKPQT
  FRNAYDIPRRNLLDHLTRMRSNLLKSTRRFLKGQDEDQVHSVPIAQMGNYQEYLKQVPSP
  LRELDPDQPRRLHTFGNPFKLDKKGMMIDEADEFVAGPQNKHKRPGEPNMQGIPKRRRCM
  SPLLRGRQQNPVVNNHIGGKGPPAPTTQAQPDLIKPLPLHKISETTNDSIIHDVVENHVA
  DQLSSDITPNAMDTEFSASSPASLLERPTNHMEALGHDHLGTNDLTVGGFLENHEEPRDK
  EQCAEENIPASSLNKGKKLMHCRSHEEVNTELKAQIMKEIRKPGRKYERIFTLLKHVQGS
  LQTRLIFLQNVIKEASRFKKRMLIEQLENFLDEIHRRANQINHINSN
• Function: Component of the Integrator (INT) complex, a complex involved in the small nuclear RNAs (snRNA) U1 and U2 transcription and in their 3'-box-dependent processing. The Integrator complex is associated with the C-terminal domain (CTD) of RNA polymerase II largest subunit (POLR2A) and is recruited to the U1 and U2 snRNAs genes (Probable). Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the INT complex. May have a tumor suppressor role; an ectopic expression suppressing tumor cell growth.
• Tissue Specificity: Widely expressed. Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.
• Reactome Pathway: RNA polymerase II transcribes snRNA genes (R-HSA-6807505)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Prostate cancer	DISF190Y	Definitive	Biomarker	[2]
Prostate carcinoma	DISMJPLE	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[5]
Eclampsia	DISWPO8U	Strong	Biomarker	[6]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Genetic Variation	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[3]
Lung neoplasm	DISVARNB	Strong	Genetic Variation	[8]
Neuroblastoma	DISVZBI4	Strong	Altered Expression	[9]
Precancerous condition	DISV06FL	Strong	Altered Expression	[10]
Nasopharyngeal carcinoma	DISAOTQ0	moderate	Biomarker	[11]
Breast neoplasm	DISNGJLM	Limited	Biomarker	[12]
Carcinoma	DISH9F1N	Limited	Altered Expression	[8]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Altered Expression	[1]
Colorectal adenoma	DISTSVHM	Limited	Altered Expression	[13]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[14]
Retinoblastoma	DISVPNPB	Limited	Altered Expression	[9]

16 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 Integrator complex subunit 6 (INTS6).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Integrator complex subunit 6 (INTS6).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Integrator complex subunit 6 (INTS6).	[17]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Integrator complex subunit 6 (INTS6).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Integrator complex subunit 6 (INTS6).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Integrator complex subunit 6 (INTS6).	[21]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Integrator complex subunit 6 (INTS6).	[22]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Integrator complex subunit 6 (INTS6).	[23]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Integrator complex subunit 6 (INTS6).	[24]
Rifampicin	DM5DSFZ	Approved	Rifampicin decreases the expression of Integrator complex subunit 6 (INTS6).	[25]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Integrator complex subunit 6 (INTS6).	[26]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Integrator complex subunit 6 (INTS6).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Integrator complex subunit 6 (INTS6).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Integrator complex subunit 6 (INTS6).	[29]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Integrator complex subunit 6 (INTS6).	[30]
ORG2058	DMH1M6N	Investigative	ORG2058 decreases the expression of Integrator complex subunit 6 (INTS6).	[31]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Integrator complex subunit 6 (INTS6).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Integrator complex subunit 6 (INTS6).	[27]

References

• [1] Small RNA-induced INTS6 gene up-regulation suppresses castration-resistant prostate cancer cells by regulating -catenin signaling.Cell Cycle. 2018;17(13):1602-1613. doi: 10.1080/15384101.2018.1475825. Epub 2018 Aug 2.
• [2] Genetic Variants of DICE1/INTS6 in German Prostate Cancer Families with Linkage to 13q14.Urol Int. 2015;95(4):386-9. doi: 10.1159/000366229. Epub 2015 Jan 31.
• [3] Integrator complex subunit 6 (INTS6) inhibits hepatocellular carcinoma growth by Wnt pathway and serve as a prognostic marker.BMC Cancer. 2017 Sep 12;17(1):644. doi: 10.1186/s12885-017-3628-3.
• [4] A double-negative feedback loop between DEAD-box protein DDX21 and Snail regulates epithelial-mesenchymal transition and metastasis in breast cancer.Cancer Lett. 2018 Nov 28;437:67-78. doi: 10.1016/j.canlet.2018.08.021. Epub 2018 Aug 27.
• [5] Expression of EIF3-p48/INT6, TID1 and Patched in cancer, a profiling of multiple tumor types and correlation of expression.J Biomed Sci. 2007 May;14(3):395-405. doi: 10.1007/s11373-007-9149-3. Epub 2007 Mar 24.
• [6] Int6/eIF3e Silencing Promotes Placenta Angiogenesis in a Rat Model of Pre-eclampsia.Sci Rep. 2018 Jun 12;8(1):8944. doi: 10.1038/s41598-018-27296-2.
• [7] Allelic loss on chromosome 13q14 and mutation in deleted in cancer 1 gene in esophageal squamous cell carcinoma.Oncogene. 2003 Jan 16;22(2):314-8. doi: 10.1038/sj.onc.1206098.
• [8] Reduced expression of INT-6/eIF3-p48 in human tumors.Int J Oncol. 2001 Jan;18(1):175-9. doi: 10.3892/ijo.18.1.175.
• [9] Overexpression of a DEAD box protein (DDX1) in neuroblastoma and retinoblastoma cell lines.J Biol Chem. 1998 Aug 14;273(33):21161-8. doi: 10.1074/jbc.273.33.21161.
• [10] Expression of truncated Int6/eIF3e in mammary alveolar epithelium leads to persistent hyperplasia and tumorigenesis.Breast Cancer Res. 2007;9(4):R42. doi: 10.1186/bcr1742.
• [11] Targeting of DICE1 tumor suppressor by Epstein-Barr virus-encoded miR-BART3* microRNA in nasopharyngeal carcinoma.Int J Cancer. 2013 Jul;133(1):79-87. doi: 10.1002/ijc.28007. Epub 2013 Feb 12.
• [12] Mammalian tumor suppressor Int6 specifically targets hypoxia inducible factor 2 alpha for degradation by hypoxia- and pVHL-independent regulation.J Biol Chem. 2007 Apr 27;282(17):12707-16. doi: 10.1074/jbc.M700423200. Epub 2007 Feb 26.
• [13] Co-overexpression of DEAD box protein rck/p54 and c-myc protein in human colorectal adenomas and the relevance of their expression in cultured cell lines.Carcinogenesis. 2001 Dec;22(12):1965-70. doi: 10.1093/carcin/22.12.1965.
• [14] Int6 expression can predict survival in early-stage non-small cell lung cancer patients.Clin Cancer Res. 2005 May 1;11(9):3198-204. doi: 10.1158/1078-0432.CCR-04-2308.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] 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.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] 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.
• [19] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [20] 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.
• [21] 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.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [24] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [25] Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
• [26] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [27] 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.
• [28] 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.
• [29] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [30] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [31] The antiproliferative effects of progestins in T47D breast cancer cells are tempered by progestin induction of the ETS transcription factor Elf5. Mol Endocrinol. 2010 Jul;24(7):1380-92. doi: 10.1210/me.2009-0516. Epub 2010 Jun 2.