Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUG02U7)

• DOT Name: KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3)
• Synonyms: RNA-binding protein T-Star; Sam68-like mammalian protein 2; SLM-2; Sam68-like phosphotyrosine protein
• Gene Name: KHDRBS3
• Related Disease:
  Colonic neoplasm
  Gastric cancer
  Medulloblastoma
  Polycystic ovarian syndrome
  Psoriasis
  Stomach cancer
  Breast cancer
  Breast carcinoma
  Neoplasm
• UniProt ID: KHDR3_HUMAN
• PDB ID: 5EL3; 5ELR; 5ELS; 5ELT; 5EMO
• Pfam ID: PF16274 ; PF16568
• Sequence:
  MEEKYLPELMAEKDSLDPSFTHALRLVNQEIEKFQKGEGKDEEKYIDVVINKNMKLGQKV
  LIPVKQFPKFNFVGKLLGPRGNSLKRLQEETLTKMSILGKGSMRDKAKEEELRKSGEAKY
  FHLNDDLHVLIEVFAPPAEAYARMGHALEEIKKFLIPDYNDEIRQAQLQELTYLNGGSEN
  ADVPVVRGKPTLRTRGVPAPAITRGRGGVTARPVGVVVPRGTPTPRGVLSTRGPVSRGRG
  LLTPRARGVPPTGYRPPPPPPTQETYGEYDYDDGYGTAYDEQSYDSYDNSYSTPAQSGAD
  YYDYGHGLSEETYDSYGQEEWTNSRHKAPSARTAKGVYRDQPYGRY
• Function: RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion. Binds preferentially to the 5'-[AU]UAAA-3' motif in vitro. Binds optimally to RNA containing 5'-[AU]UAA-3' as a bipartite motif spaced by more than 15 nucleotides. Binds poly(A). RNA-binding abilities are down-regulated by tyrosine kinase PTK6. Involved in splice site selection of vascular endothelial growth factor. In vitro regulates CD44 alternative splicing by direct binding to purine-rich exonic enhancer. Can regulate alternative splicing of neurexins NRXN1-3 in the laminin G-like domain 6 containing the evolutionary conserved neurexin alternative spliced segment 4 (AS4) involved in neurexin selective targeting to postsynaptic partners such as neuroligins and LRRTM family members. Targeted, cell-type specific splicing regulation of NRXN1 at AS4 is involved in neuronal glutamatergic synapse function and plasticity. May regulate expression of KHDRBS2/SLIM-1 in defined brain neuron populations by modifying its alternative splicing. Can bind FABP9 mRNA. May play a role as a negative regulator of cell growth. Inhibits cell proliferation; (Microbial infection) Involved in post-transcriptional regulation of HIV-1 gene expression.
• Tissue Specificity: Ubiquitous with higher expression in testis, skeletal muscle and brain. Expressed in the kidney only in podocytes, the glomerular epithelial cells of the kidney. Strongly expressed after meiosis.
• Reactome Pathway: PTK6 Regulates Proteins Involved in RNA Processing (R-HSA-8849468)

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[1]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[3]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Altered Expression	[4]
Psoriasis	DIS59VMN	Strong	Altered Expression	[5]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[2]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[6]
Neoplasm	DISZKGEW	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[10]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[12]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[15]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[16]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[17]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[20]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[22]

2 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 decreases the methylation of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of KH domain-containing, RNA-binding, signal transduction-associated protein 3 (KHDRBS3).	[21]

References

• [1] Expression of T-STAR gene is associated with regulation of telomerase activity in human colon cancer cell line HCT-116.World J Gastroenterol. 2006 Jul 7;12(25):4056-60. doi: 10.3748/wjg.v12.i25.4056.
• [2] SerpinB5 interacts with KHDRBS3 and FBXO32 in gastric cancer cells.Oncol Rep. 2011 Nov;26(5):1115-20. doi: 10.3892/or.2011.1369. Epub 2011 Jul 1.
• [3] Amplification and overexpression of Hsa-miR-30b, Hsa-miR-30d and KHDRBS3 at 8q24.22-q24.23 in medulloblastoma.PLoS One. 2009 Jul 7;4(7):e6159. doi: 10.1371/journal.pone.0006159.
• [4] Genome-wide association study identified new susceptibility loci for polycystic ovary syndrome.Hum Reprod. 2015 Mar;30(3):723-31. doi: 10.1093/humrep/deu352. Epub 2015 Jan 8.
• [5] Levels of miR-31 and its target genes in dermal mesenchymal cells of patients with psoriasis.Int J Dermatol. 2019 Feb;58(2):198-204. doi: 10.1111/ijd.14197. Epub 2018 Sep 9.
• [6] Nuclear T-STAR protein expression correlates with HER2 status, hormone receptor negativity and prolonged recurrence free survival in primary breast cancer and decreased cancer cell growth in vitro.PLoS One. 2013 Jul 29;8(7):e70596. doi: 10.1371/journal.pone.0070596. Print 2013.
• [7] Encapsulation of c-myc antisense oligodeoxynucleotides in lipid particles improves antitumoral efficacy in vivo in a human melanoma line.Cancer Gene Ther. 2001 Jun;8(6):459-68. doi: 10.1038/sj.cgt.7700326.
• [8] 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.
• [9] 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.
• [10] The thioxotriazole copper(II) complex A0 induces endoplasmic reticulum stress and paraptotic death in human cancer cells. J Biol Chem. 2009 Sep 4;284(36):24306-19.
• [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] 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.
• [13] 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.
• [14] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [15] Gene expression profiling of rheumatoid arthritis synovial cells treated with antirheumatic drugs. J Biomol Screen. 2007 Apr;12(3):328-40. doi: 10.1177/1087057107299261. Epub 2007 Mar 22.
• [16] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] 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.
• [22] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.