Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9ROJCL)

• DOT Name: Splicing factor 45 (RBM17)
• Synonyms: 45 kDa-splicing factor; RNA-binding motif protein 17
• Gene Name: RBM17
• Related Disease:
  Advanced cancer
  Carcinoma
  Glioma
  Hypopharyngeal carcinoma
  Neoplasm
  Spinocerebellar ataxia type 1
  Li-Fraumeni syndrome
  Autosomal dominant cerebellar ataxia type II
  Spinocerebellar ataxia type 2
  Spinocerebellar ataxia type 5
  Spinocerebellar ataxia type 6
  Type-1 diabetes
• UniProt ID: SPF45_HUMAN
• PDB ID: 2PE8; 2PEH; 5LSO; 6HIP
• Pfam ID: PF01585 ; PF00076
• Sequence:
  MSLYDDLGVETSDSKTEGWSKNFKLLQSQLQVKKAALTQAKSQRTKQSTVLAPVIDLKRG
  GSSDDRQIVDTPPHVAAGLKDPVPSGFSAGEVLIPLADEYDPMFPNDYEKVVKRQREERQ
  RQRELERQKEIEEREKRRKDRHEASGFARRPDPDSDEDEDYERERRKRSMGGAAIAPPTS
  LVEKDKELPRDFPYEEDSRPRSQSSKAAIPPPVYEEQDRPRSPTGPSNSFLANMGGTVAH
  KIMQKYGFREGQGLGKHEQGLSTALSVEKTSKRGGKIIVGDATEKDASKKSDSNPLTEIL
  KCPTKVVLLRNMVGAGEVDEDLEVETKEECEKYGKVGKCVIFEIPGAPDDEAVRIFLEFE
  RVESAIKAVVDLNGRYFGGRVVKACFYNLDKFRVLDLAEQV
• Function: Splice factor that binds to the single-stranded 3'AG at the exon/intron border and promotes its utilization in the second catalytic step. Involved in the regulation of alternative splicing and the utilization of cryptic splice sites. Promotes the utilization of a cryptic splice site created by the beta-110 mutation in the HBB gene. The resulting frameshift leads to sickle cell anemia.
• KEGG Pathway: Spliceosome (hsa03040)
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[2]
Glioma	DIS5RPEH	Strong	Biomarker	[3]
Hypopharyngeal carcinoma	DISLOSB4	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Biomarker	[2]
Spinocerebellar ataxia type 1	DISF7BO2	Strong	Biomarker	[4]
Li-Fraumeni syndrome	DISR64XA	Disputed	Biomarker	[5]
Autosomal dominant cerebellar ataxia type II	DIS0PM39	Limited	Biomarker	[4]
Spinocerebellar ataxia type 2	DISF7WDI	Limited	Biomarker	[4]
Spinocerebellar ataxia type 5	DISPYXJ0	Limited	Biomarker	[4]
Spinocerebellar ataxia type 6	DISH7224	Limited	Biomarker	[4]
Type-1 diabetes	DIS7HLUB	Limited	Genetic Variation	[6]

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Etoposide	DMNH3PG	Approved	Splicing factor 45 (RBM17) decreases the response to substance of Etoposide.	[20]
Gemcitabine	DMSE3I7	Approved	Splicing factor 45 (RBM17) decreases the response to substance of Gemcitabine.	[20]
Mitoxantrone	DMM39BF	Approved	Splicing factor 45 (RBM17) decreases the response to substance of Mitoxantrone.	[20]
Pemetrexed	DMMX2E6	Approved	Splicing factor 45 (RBM17) decreases the response to substance of Pemetrexed.	[20]
Vinorelbine	DMVXFYE	Approved	Splicing factor 45 (RBM17) decreases the response to substance of Vinorelbine.	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Splicing factor 45 (RBM17).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Splicing factor 45 (RBM17).	[17]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Splicing factor 45 (RBM17).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Splicing factor 45 (RBM17).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Splicing factor 45 (RBM17).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Splicing factor 45 (RBM17).	[8]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Splicing factor 45 (RBM17).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Splicing factor 45 (RBM17).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Splicing factor 45 (RBM17).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Splicing factor 45 (RBM17).	[12]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Splicing factor 45 (RBM17).	[13]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Splicing factor 45 (RBM17).	[14]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Splicing factor 45 (RBM17).	[15]
DNCB	DMDTVYC	Phase 2	DNCB decreases the expression of Splicing factor 45 (RBM17).	[16]

References

• [1] Downregulation of RNA binding motif protein 17 expression inhibits proliferation of hypopharyngeal carcinoma FaDu cells.Oncol Lett. 2018 Apr;15(4):5680-5684. doi: 10.3892/ol.2018.8012. Epub 2018 Feb 9.
• [2] Human SPF45, a splicing factor, has limited expression in normal tissues, is overexpressed in many tumors, and can confer a multidrug-resistant phenotype to cells.Am J Pathol. 2003 Nov;163(5):1781-90. doi: 10.1016/S0002-9440(10)63538-9.
• [3] RBM17 controls apoptosis and proliferation to promote Glioma progression.Biochem Biophys Res Commun. 2018 Oct 20;505(1):20-28. doi: 10.1016/j.bbrc.2018.09.056. Epub 2018 Sep 15.
• [4] Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1.Nature. 2008 Apr 10;452(7188):713-8. doi: 10.1038/nature06731. Epub 2008 Mar 12.
• [5] Methylation profile of the promoter CpG islands of 14 "drug-resistance" genes in hepatocellular carcinoma.World J Gastroenterol. 2004 Dec 1;10(23):3433-40. doi: 10.3748/wjg.v10.i23.3433.
• [6] Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes.Nat Genet. 2007 Sep;39(9):1074-82. doi: 10.1038/ng2102. Epub 2007 Aug 5.
• [7] 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.
• [8] 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.
• [9] Nuclear proteome analysis of cisplatin-treated HeLa cells. Mutat Res. 2010 Sep 10;691(1-2):1-8. doi: 10.1016/j.mrfmmm.2010.06.002. Epub 2010 Jun 9.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
• [15] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [16] Microarray analyses in dendritic cells reveal potential biomarkers for chemical-induced skin sensitization. Mol Immunol. 2007 May;44(12):3222-33.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] Human splicing factor SPF45 (RBM17) confers broad multidrug resistance to anticancer drugs when overexpressed--a phenotype partially reversed by selective estrogen receptor modulators. Cancer Res. 2005 Aug 1;65(15):6593-600. doi: 10.1158/0008-5472.CAN-03-3675.