Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4F98TK)

• DOT Name: ATP-dependent RNA helicase DHX15 (DHX15)
• Synonyms: EC 3.6.4.13; ATP-dependent RNA helicase #46; DEAH box protein 15; Splicing factor Prp43; hPrp43
• Gene Name: DHX15
• Related Disease:
  Acute graft versus host disease
  Acute lymphocytic leukaemia
  Advanced cancer
  Anca-associated vasculitis
  Castration-resistant prostate carcinoma
  Gastric cancer
  Glioma
  Graft-versus-host disease
  Hepatocellular carcinoma
  Lung adenocarcinoma
  Non-small-cell lung cancer
  Prostate cancer
  Prostate carcinoma
  Stomach cancer
  Hepatitis B virus infection
  Neoplasm
  Acute myelogenous leukaemia
• UniProt ID: DHX15_HUMAN
• PDB ID: 5XDR; 6ID1; 6SH6; 6SH7; 8EJM
• EC Number: 3.6.4.13
• Pfam ID: PF00270 ; PF21010 ; PF04408 ; PF00271 ; PF07717
• Sequence:
  MSKRHRLDLGEDYPSGKKRAGTDGKDRDRDRDREDRSKDRDRERDRGDREREREKEKEKE
  LRASTNAMLISAGLPPLKASHSAHSTHSAHSTHSTHSAHSTHAGHAGHTSLPQCINPFTN
  LPHTPRYYDILKKRLQLPVWEYKDRFTDILVRHQSFVLVGETGSGKTTQIPQWCVEYMRS
  LPGPKRGVACTQPRRVAAMSVAQRVADEMDVMLGQEVGYSIRFEDCSSAKTILKYMTDGM
  LLREAMNDPLLERYGVIILDEAHERTLATDILMGVLKEVVRQRSDLKVIVMSATLDAGKF
  QIYFDNCPLLTIPGRTHPVEIFYTPEPERDYLEAAIRTVIQIHMCEEEEGDLLLFLTGQE
  EIDEACKRIKREVDDLGPEVGDIKIIPLYSTLPPQQQQRIFEPPPPKKQNGAIGRKVVVS
  TNIAETSLTIDGVVFVIDPGFAKQKVYNPRIRVESLLVTAISKASAQQRAGRAGRTRPGK
  CFRLYTEKAYKTEMQDNTYPEILRSNLGSVVLQLKKLGIDDLVHFDFMDPPAPETLMRAL
  ELLNYLAALNDDGDLTELGSMMAEFPLDPQLAKMVIASCDYNCSNEVLSITAMLSVPQCF
  VRPTEAKKAADEAKMRFAHIDGDHLTLLNVYHAFKQNHESVQWCYDNFINYRSLMSADNV
  RQQLSRIMDRFNLPRRSTDFTSRDYYINIRKALVTGYFMQVAHLERTGHYLTVKDNQVVQ
  LHPSTVLDHKPEWVLYNEFVLTTKNYIRTCTDIKPEWLVKIAPQYYDMSNFPQCEAKRQL
  DRIIAKLQSKEYSQY
• Function: RNA helicase involved in mRNA processing and antiviral innate immunity. Pre-mRNA processing factor involved in disassembly of spliceosomes after the release of mature mRNA. In cooperation with TFIP11 seem to be involved in the transition of the U2, U5 and U6 snRNP-containing IL complex to the snRNP-free IS complex leading to efficient debranching and turnover of excised introns. Plays a key role in antiviral innate immunity by promoting both MAVS-dependent signaling and NLRP6 inflammasome. Acts as an RNA virus sensor: recognizes and binds viral double stranded RNA (dsRNA) and activates the MAVS-dependent signaling to produce interferon-beta and interferon lambda-3 (IFNL3). Involved in intestinal antiviral innate immunity together with NLRP6: recognizes and binds viral dsRNA and promotes activation of the NLRP6 inflammasome in intestinal epithelial cells to restrict infection by enteric viruses. The NLRP6 inflammasome acts by promoting maturation and secretion of IL18 in the extracellular milieu. Also involved in antibacterial innate immunity by promoting Wnt-induced antimicrobial protein expression in Paneth cells.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute graft versus host disease	DIS8KLVM	Strong	Biomarker	[1]
Acute lymphocytic leukaemia	DISPX75S	Strong	Altered Expression	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Anca-associated vasculitis	DISU3CNU	Strong	Biomarker	[4]
Castration-resistant prostate carcinoma	DISVGAE6	Strong	Altered Expression	[5]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[6]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Graft-versus-host disease	DIS0QADF	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[7]
Lung adenocarcinoma	DISD51WR	Strong	Genetic Variation	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Prostate cancer	DISF190Y	Strong	Altered Expression	[5]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[5]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[6]
Hepatitis B virus infection	DISLQ2XY	moderate	Altered Expression	[7]
Neoplasm	DISZKGEW	moderate	Altered Expression	[7]
Acute myelogenous leukaemia	DISCSPTN	Disputed	Genetic Variation	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	ATP-dependent RNA helicase DHX15 (DHX15) affects the response to substance of Methotrexate.	[26]

14 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 ATP-dependent RNA helicase DHX15 (DHX15).	[11]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[15]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[13]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[16]
Marinol	DM70IK5	Approved	Marinol increases the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[17]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[18]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[19]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[21]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[22]
Deguelin	DMXT7WG	Investigative	Deguelin increases the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[23]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[24]
PP-242	DM2348V	Investigative	PP-242 decreases the expression of ATP-dependent RNA helicase DHX15 (DHX15).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the methylation of ATP-dependent RNA helicase DHX15 (DHX15).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP-dependent RNA helicase DHX15 (DHX15).	[20]

References

• [1] DPB1 disparities contribute to severe GVHD and reduced patient survival after unrelated donor bone marrow transplantation.Bone Marrow Transplant. 2002 Oct;30(8):497-502. doi: 10.1038/sj.bmt.1703658.
• [2] ETS1 and SP1 drive DHX15 expression in acute lymphoblastic leukaemia.J Cell Mol Med. 2018 May;22(5):2612-2621. doi: 10.1111/jcmm.13525. Epub 2018 Mar 7.
• [3] RNA helicase DHX15 acts as a tumour suppressor in glioma.Br J Cancer. 2017 Oct 24;117(9):1349-1359. doi: 10.1038/bjc.2017.273. Epub 2017 Aug 22.
• [4] HLA allele variation as a potential explanation for the geographical distribution of granulomatosis with polyangiitis.Rheumatology (Oxford). 2015 Feb;54(2):359-62. doi: 10.1093/rheumatology/keu321. Epub 2014 Aug 28.
• [5] DHX15 is up-regulated in castration-resistant prostate cancer and required for androgen receptor sensitivity to low DHT concentrations.Prostate. 2019 May;79(6):657-666. doi: 10.1002/pros.23773. Epub 2019 Feb 3.
• [6] Cerium oxide nanoparticles inhibit the migration and proliferation of gastric cancer by increasing DHX15 expression.Int J Nanomedicine. 2016 Jul 15;11:3023-34. doi: 10.2147/IJN.S103648. eCollection 2016.
• [7] Overexpression and clinical relevance of the RNA helicase DHX15 in hepatocellular carcinoma.Hum Pathol. 2019 Feb;84:213-220. doi: 10.1016/j.humpath.2018.10.006. Epub 2018 Oct 17.
• [8] Vitamin D Supplementation and Survival of Patients with Non-small Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Trial.Clin Cancer Res. 2018 Sep 1;24(17):4089-4097. doi: 10.1158/1078-0432.CCR-18-0483. Epub 2018 Jul 17.
• [9] Long Non-coding RNA JHDM1D-AS1 Interacts with DHX15 Protein to Enhance Non-Small-Cell Lung Cancer Growth and Metastasis.Mol Ther Nucleic Acids. 2019 Dec 6;18:831-840. doi: 10.1016/j.omtn.2019.09.028. Epub 2019 Oct 10.
• [10] Splicing factor DHX15 affects tp53 and mdm2 expression via alternate splicing and promoter usage.Hum Mol Genet. 2019 Dec 15;28(24):4173-4185. doi: 10.1093/hmg/ddz261.
• [11] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [12] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [13] DHX15 is associated with poor prognosis in acute myeloid leukemia (AML) and regulates cell apoptosis via the NF-kB signaling pathway. Oncotarget. 2017 Aug 16;8(52):89643-89654. doi: 10.18632/oncotarget.20288. eCollection 2017 Oct 27.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 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.
• [16] 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.
• [17] Cannabis-induced cytotoxicity in leukemic cell lines: the role of the cannabinoid receptors and the MAPK pathway. Blood. 2005 Feb 1;105(3):1214-21. doi: 10.1182/blood-2004-03-1182. Epub 2004 Sep 28.
• [18] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [19] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [20] 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.
• [21] 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.
• [22] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [23] 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.
• [24] 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.
• [25] Marine biogenics in sea spray aerosols interact with the mTOR signaling pathway. Sci Rep. 2019 Jan 24;9(1):675.
• [26] 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.