Details of Drug Off-Target (DOT)

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

• DOT Name: KH domain-containing RNA-binding protein QKI (QKI)
• Synonyms: Protein quaking; Hqk; HqkI
• Gene Name: QKI
• Related Disease:
  Bone osteosarcoma
  Osteosarcoma
  Advanced cancer
  Astrocytoma
  Cervical cancer
  Cervical carcinoma
  Clear cell renal carcinoma
  Colorectal carcinoma
  Esophageal squamous cell carcinoma
  Kidney cancer
  Lung cancer
  Lung carcinoma
  Major depressive disorder
  Mental disorder
  Multiple sclerosis
  Myocardial infarction
  Neoplasm
  Neuromyelitis optica
  Ovarian neoplasm
  Renal carcinoma
  Head-neck squamous cell carcinoma
  Lung adenocarcinoma
  Pancreatic cancer
  Adult glioblastoma
  Anxiety disorder
  Glioblastoma multiforme
  Glioma
  Intellectual disability
  Intellectual disability, autosomal dominant 40
  Malignant glioma
  Mixed glioma
  Prostate cancer
  Prostate carcinoma
• UniProt ID: QKI_HUMAN
• PDB ID: 4JVH
• Pfam ID: PF00013 ; PF16551 ; PF16544
• Sequence:
  MVGEMETKEKPKPTPDYLMQLMNDKKLMSSLPNFCGIFNHLERLLDEEISRVRKDMYNDT
  LNGSTEKRSAELPDAVGPIVQLQEKLYVPVKEYPDFNFVGRILGPRGLTAKQLEAETGCK
  IMVRGKGSMRDKKKEEQNRGKPNWEHLNEDLHVLITVEDAQNRAEIKLKRAVEEVKKLLV
  PAAEGEDSLKKMQLMELAILNGTYRDANIKSPALAFSLAATAQAAPRIITGPAPVLPPAA
  LRTPTPAGPTIMPLIRQIQTAVMPNGTPHPTAAIVPPGPEAGLIYTPYEYPYTLAPATSI
  LEYPIEPSGVLGAVATKVRRHDMRVHPYQRIVTADRAATGN
• Function: RNA reader protein, which recognizes and binds specific RNAs, thereby regulating RNA metabolic processes, such as pre-mRNA splicing, circular RNA (circRNA) formation, mRNA export, mRNA stability and/or translation. Involved in various cellular processes, such as mRNA storage into stress granules, apoptosis, lipid deposition, interferon response, glial cell fate and development. Binds to the 5'-NACUAAY-N(1,20)-UAAY-3' RNA core sequence. Acts as a mRNA modification reader that specifically recognizes and binds mRNA transcripts modified by internal N(7)-methylguanine (m7G). Promotes the formation of circular RNAs (circRNAs) during the epithelial to mesenchymal transition and in cardiomyocytes: acts by binding to sites flanking circRNA-forming exons. CircRNAs are produced by back-splicing circularization of pre-mRNAs. Plays a central role in myelinization via 3 distinct mechanisms. First, acts by protecting and promoting stability of target mRNAs such as MBP, SIRT2 and CDKN1B, which promotes oligodendrocyte differentiation. Second, participates in mRNA transport by regulating the nuclear export of MBP mRNA. Finally, indirectly regulates mRNA splicing of MAG pre-mRNA during oligodendrocyte differentiation by acting as a negative regulator of MAG exon 12 alternative splicing: acts by binding to HNRNPA1 mRNA splicing factor, preventing its translation. Involved in microglia differentiation and remyelination by regulating microexon alternative splicing of the Rho GTPase pathway. Involved in macrophage differentiation: promotes monocyte differentiation by regulating pre-mRNA splicing in naive peripheral blood monocytes. Acts as an important regulator of muscle development: required for the contractile function of cardiomyocytes by regulating alternative splicing of cardiomyocyte transcripts. Acts as a negative regulator of thermogenesis by decreasing stability, nuclear export and translation of mRNAs encoding PPARGC1A and UCP1. Also required for visceral endoderm function and blood vessel development. May also play a role in smooth muscle development. In addition to its RNA-binding activity, also acts as a nuclear transcription coactivator for SREBF2/SREBP2; [Isoform QKI5]: Nuclear isoform that acts as an indirect regulator of mRNA splicing. Regulates mRNA splicing of MAG pre-mRNA by inhibiting translation of HNRNPA1 mRNA, thereby preventing MAG exon 12 alternative splicing. Involved in oligodendrocyte differentiation by promoting stabilization of SIRT2 mRNA. Acts as a negative regulator of the interferon response by binding to MAVS mRNA, downregulating its expression. Also inhibits the interferon response by binding to fibrinectin FN1 pre-mRNA, repressing EDA exon inclusion in FN1. Delays macrophage differentiation by binding to CSF1R mRNA, promoting its degradation. In addition to its RNA-binding activity, also acts as a nuclear transcription coactivator for SREBF2/SREBP2, promoting SREBF2/SREBP2-dependent cholesterol biosynthesis. SREBF2/SREBP2-dependent cholesterol biosynthesis participates to myelinization and is required for eye lens transparency; [Isoform QKI6]: Cytosolic isoform that specifically recognizes and binds mRNA transcripts modified by internal N(7)-methylguanine (m7G). Interaction with G3BP1 promotes localization of m7G-containing mRNAs into stress granules in response to stress, thereby suppressing their translation. Acts as a translational repressor for HNRNPA1 and GLI1. Translation inhibition of HNRNPA1 during oligodendrocyte differentiation prevents inclusion of exon 12 in MAG pre-mRNA splicing. Involved in astrocyte differentiation by regulating translation of target mRNAs; [Isoform QKI7]: Cytosolic isoform that specifically recognizes and binds mRNA transcripts modified by internal N(7)-methylguanine (m7G). Interaction with G3BP1 promotes localization of m7G-containing mRNAs into stress granules in response to stress, thereby suppressing their translation. Acts as a negative regulator of angiogenesis by binding to mRNAs encoding CDH5, NLGN1 and TNFAIP6, promoting their degradation. Can also induce apoptosis in the cytoplasm. Heterodimerization with other isoforms results in nuclear translocation of isoform QKI7 and suppression of apoptosis. Also binds some microRNAs: promotes stabilitation of miR-122 by mediating recruitment of poly(A) RNA polymerase TENT2, leading to 3' adenylation and stabilization of miR-122.
• Tissue Specificity: Expressed in the frontal cortex of brain. Down-regulated in the brain of schizophrenic patients.
• Reactome Pathway: Signaling by BRAF and RAF1 fusions (R-HSA-6802952)

Molecular Interaction Atlas (MIA) of This DOT

33 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Biomarker	[1]
Osteosarcoma	DISLQ7E2	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Astrocytoma	DISL3V18	Strong	Genetic Variation	[3]
Cervical cancer	DISFSHPF	Strong	Altered Expression	[4]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[6]
Kidney cancer	DISBIPKM	Strong	Biomarker	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Major depressive disorder	DIS4CL3X	Strong	Altered Expression	[9]
Mental disorder	DIS3J5R8	Strong	Altered Expression	[9]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[10]
Myocardial infarction	DIS655KI	Strong	Genetic Variation	[11]
Neoplasm	DISZKGEW	Strong	Biomarker	[12]
Neuromyelitis optica	DISBFGKL	Strong	Biomarker	[10]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[13]
Renal carcinoma	DISER9XT	Strong	Biomarker	[7]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[14]
Lung adenocarcinoma	DISD51WR	moderate	Biomarker	[15]
Pancreatic cancer	DISJC981	moderate	Biomarker	[16]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[17]
Anxiety disorder	DISBI2BT	Limited	Biomarker	[18]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[17]
Glioma	DIS5RPEH	Limited	Biomarker	[19]
Intellectual disability	DISMBNXP	Limited	Biomarker	[20]
Intellectual disability, autosomal dominant 40	DISAI0IH	Limited	Autosomal dominant	[20]
Malignant glioma	DISFXKOV	Limited	Biomarker	[19]
Mixed glioma	DIS64UY3	Limited	Biomarker	[19]
Prostate cancer	DISF190Y	Limited	Biomarker	[21]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[21]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Topotecan	DMP6G8T	Approved	KH domain-containing RNA-binding protein QKI (QKI) affects the response to substance of Topotecan.	[37]

2 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 KH domain-containing RNA-binding protein QKI (QKI).	[22]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of KH domain-containing RNA-binding protein QKI (QKI).	[28]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[24]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[25]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[26]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[27]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[29]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[30]
Haloperidol	DM96SE0	Approved	Haloperidol increases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[32]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[35]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of KH domain-containing RNA-binding protein QKI (QKI).	[36]

References

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• [2] RNA-binding protein QKI regulates contact inhibition via Yes-associate protein in ccRCC.Acta Biochim Biophys Sin (Shanghai). 2019 Jan 1;51(1):9-19. doi: 10.1093/abbs/gmy142.
• [3] Tyrosine receptor kinase B is a drug target in astrocytomas.Neuro Oncol. 2017 Jan;19(1):22-30. doi: 10.1093/neuonc/now139. Epub 2016 Jul 10.
• [4] Inhibition of miR-574-5p suppresses cell growth and metastasis and enhances chemosensitivity by targeting RNA binding protein QKI in cervical cancer cells.Naunyn Schmiedebergs Arch Pharmacol. 2020 Jun;393(6):951-966. doi: 10.1007/s00210-019-01772-6. Epub 2019 Nov 30.
• [5] Clinical Significance of Methylation and Reduced Expression of the Quaking Gene in Colorectal Cancer.Anticancer Res. 2017 Feb;37(2):489-498. doi: 10.21873/anticanres.11341.
• [6] MiR-143-3p functions as a tumor suppressor by regulating cell proliferation, invasion and epithelial-mesenchymal transition by targeting QKI-5 in esophageal squamous cell carcinoma.Mol Cancer. 2016 Jun 29;15(1):51. doi: 10.1186/s12943-016-0533-3.
• [7] RNA-binding protein QKI-5 inhibits the proliferation of clear cell renal cell carcinoma via post-transcriptional stabilization of RASA1 mRNA.Cell Cycle. 2016 Nov 16;15(22):3094-3104. doi: 10.1080/15384101.2016.1235103. Epub 2016 Oct 21.
• [8] Quaking-5 suppresses aggressiveness of lung cancer cells through inhibiting -catenin signaling pathway.Oncotarget. 2017 Jul 7;8(47):82174-82184. doi: 10.18632/oncotarget.19066. eCollection 2017 Oct 10.
• [9] Characterization of QKI gene expression, genetics, and epigenetics in suicide victims with major depressive disorder.Biol Psychiatry. 2009 Nov 1;66(9):824-31. doi: 10.1016/j.biopsych.2009.05.010. Epub 2009 Jul 9.
• [10] QKI-V5 is downregulated in CNS inflammatory demyelinating diseases.Mult Scler Relat Disord. 2020 Apr;39:101881. doi: 10.1016/j.msard.2019.101881. Epub 2019 Dec 4.
• [11] Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium.PLoS One. 2016 Mar 7;11(3):e0144997. doi: 10.1371/journal.pone.0144997. eCollection 2016.
• [12] Frameshift mutation of candidate tumor suppressor genes QK1 and TMEFF2 in gastric and colorectal cancers.Cancer Biomark. 2019;24(1):1-6. doi: 10.3233/CBM-160559.
• [13] Tumor microenvironment-associated modifications of alternative splicing.RNA. 2014 Feb;20(2):189-201. doi: 10.1261/rna.042168.113. Epub 2013 Dec 11.
• [14] QKI, a miR-200 target gene, suppresses epithelial-to-mesenchymal transition and tumor growth.Int J Cancer. 2019 Sep 15;145(6):1585-1595. doi: 10.1002/ijc.32372. Epub 2019 May 14.
• [15] A regulatory circuit of circ-MTO1/miR-17/QKI-5 inhibits the proliferation of lung adenocarcinoma.Cancer Biol Ther. 2019;20(8):1127-1135. doi: 10.1080/15384047.2019.1598762. Epub 2019 Apr 12.
• [16] Effects of RNA binding protein QKI on pancreatic cancer ductal epithelial cells and surrounding activation fibroblasts.J Cell Biochem. 2019 Jul;120(7):11551-11561. doi: 10.1002/jcb.28435. Epub 2019 Apr 10.
• [17] Overexpression of miR-29a reduces the oncogenic properties of glioblastoma stem cells by downregulating Quaking gene isoform 6.Oncotarget. 2017 Apr 11;8(15):24949-24963. doi: 10.18632/oncotarget.15327.
• [18] Convergent functional genomics of anxiety disorders: translational identification of genes, biomarkers, pathways and mechanisms.Transl Psychiatry. 2011 May 24;1(5):e9. doi: 10.1038/tp.2011.9.
• [19] MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism.Nat Genet. 2016 Mar;48(3):273-82. doi: 10.1038/ng.3500. Epub 2016 Feb 1.
• [20] Haploinsufficiency of the gene Quaking (QKI) is associated with the 6q terminal deletion syndrome. Am J Med Genet A. 2010 Feb;152A(2):319-26. doi: 10.1002/ajmg.a.33202.
• [21] The tumor suppressing effects of QKI-5 in prostate cancer: a novel diagnostic and prognostic protein.Cancer Biol Ther. 2014 Jan;15(1):108-18. doi: 10.4161/cbt.26722. Epub 2013 Oct 23.
• [22] 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.
• [23] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [24] 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.
• [25] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [26] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [27] 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.
• [28] 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.
• [29] 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.
• [30] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [31] Haloperidol changes mRNA expression of a QKI splice variant in human astrocytoma cells. BMC Pharmacol. 2009 Mar 31;9:6. doi: 10.1186/1471-2210-9-6.
• [32] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [33] 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.
• [34] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [35] 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.
• [36] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [37] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.