Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCMPTF9)

• DOT Name: RNA-binding protein 39 (RBM39)
• Synonyms: CAPER alpha; CAPERalpha; Hepatocellular carcinoma protein 1; RNA-binding motif protein 39; RNA-binding region-containing protein 2; Splicing factor HCC1
• Gene Name: RBM39
• Related Disease:
  Colorectal adenoma
  Colorectal carcinoma
  Acute myelogenous leukaemia
  Breast cancer
  Breast carcinoma
  Chronic kidney disease
  Chronic renal failure
  Dilated cardiomyopathy 1A
  Ductal breast carcinoma in situ
  End-stage renal disease
  Hepatitis B virus infection
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Invasive ductal breast carcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Non-small-cell lung cancer
  Pancreatic adenocarcinoma
  Plasma cell myeloma
  Advanced cancer
  Castration-resistant prostate carcinoma
• UniProt ID: RBM39_HUMAN
• PDB ID: 2JRS; 2MHN; 4OO6; 4OZ0; 4OZ1; 4YUD; 6PAI; 6Q0R; 6Q0V; 6Q0W; 6SJ7; 6UD7; 6UE5; 7Q33
• Pfam ID: PF15519 ; PF00076
• Sequence:
  MADDIDIEAMLEAPYKKDENKLSSANGHEERSKKRKKSKSRSRSHERKRSKSKERKRSRD
  RERKKSKSRERKRSRSKERRRSRSRSRDRRFRGRYRSPYSGPKFNSAIRGKIGLPHSIKL
  SRRRSRSKSPFRKDKSPVREPIDNLTPEERDARTVFCMQLAARIRPRDLEEFFSTVGKVR
  DVRMISDRNSRRSKGIAYVEFVDVSSVPLAIGLTGQRVLGVPIIVQASQAEKNRAAAMAN
  NLQKGSAGPMRLYVGSLHFNITEDMLRGIFEPFGRIESIQLMMDSETGRSKGYGFITFSD
  SECAKKALEQLNGFELAGRPMKVGHVTERTDASSASSFLDSDELERTGIDLGTTGRLQLM
  ARLAEGTGLQIPPAAQQALQMSGSLAFGAVAEFSFVIDLQTRLSQQTEASALAAAASVQP
  LATQCFQLSNMFNPQTEEEVGWDTEIKDDVIEECNKHGGVIHIYVDKNSAQGNVYVKCPS
  IAAAIAAVNALHGRWFAGKMITAAYVPLPTYHNLFPDSMTATQLLVPSRR
• Function: RNA-binding protein that acts as a pre-mRNA splicing factor. Acts by promoting exon inclusion via regulation of exon cassette splicing. Also acts as a transcriptional coactivator for steroid nuclear receptors ESR1/ER-alpha and ESR2/ER-beta, and JUN/AP-1, independently of the pre-mRNA splicing factor activity.
• Tissue Specificity: Widely expressed. Highly expressed in pancreas, skeletal muscle, lung and brain . Expressed at intermediate level in kidney, liver and heart .
• Reactome Pathway: mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colorectal adenoma	DISTSVHM	Definitive	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Definitive	Biomarker	[1]
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[4]
Chronic renal failure	DISGG7K6	Strong	Biomarker	[4]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[3]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Altered Expression	[3]
End-stage renal disease	DISXA7GG	Strong	Biomarker	[4]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[5]
Hepatitis C virus infection	DISQ0M8R	Strong	Genetic Variation	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[6]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[3]
Lung cancer	DISCM4YA	Strong	Biomarker	[7]
Lung carcinoma	DISTR26C	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[9]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[10]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[11]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[12]
Castration-resistant prostate carcinoma	DISVGAE6	Limited	Biomarker	[13]

15 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 RNA-binding protein 39 (RBM39).	[14]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of RNA-binding protein 39 (RBM39).	[15]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of RNA-binding protein 39 (RBM39).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of RNA-binding protein 39 (RBM39).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of RNA-binding protein 39 (RBM39).	[18]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of RNA-binding protein 39 (RBM39).	[19]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of RNA-binding protein 39 (RBM39).	[20]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of RNA-binding protein 39 (RBM39).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of RNA-binding protein 39 (RBM39).	[23]
Torcetrapib	DMDHYM7	Discontinued in Phase 2	Torcetrapib increases the expression of RNA-binding protein 39 (RBM39).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of RNA-binding protein 39 (RBM39).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of RNA-binding protein 39 (RBM39).	[27]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of RNA-binding protein 39 (RBM39).	[28]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of RNA-binding protein 39 (RBM39).	[29]
Bilirubin	DMI0V4O	Investigative	Bilirubin decreases the expression of RNA-binding protein 39 (RBM39).	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of RNA-binding protein 39 (RBM39).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of RNA-binding protein 39 (RBM39).	[24]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of RNA-binding protein 39 (RBM39).	[24]

References

• [1] CSE1L, DIDO1 and RBM39 in colorectal adenoma to carcinoma progression.Cell Oncol (Dordr). 2012 Aug;35(4):293-300. doi: 10.1007/s13402-012-0088-2. Epub 2012 Jun 19.
• [2] Targeting an RNA-Binding Protein Network in Acute Myeloid Leukemia.Cancer Cell. 2019 Mar 18;35(3):369-384.e7. doi: 10.1016/j.ccell.2019.01.010. Epub 2019 Feb 21.
• [3] CAPER, a novel regulator of human breast cancer progression.Cell Cycle. 2014;13(8):1256-64. doi: 10.4161/cc.28156. Epub 2014 Feb 17.
• [4] HCC-1, a novel chemokine from human plasma.J Exp Med. 1996 Jan 1;183(1):295-9. doi: 10.1084/jem.183.1.295.
• [5] Hepatitis C virus core protein fused to hepatitis B virus core antigen for serological diagnosis of both hepatitis C and hepatitis B infections by ELISA.J Med Virol. 1999 Feb;57(2):104-10.
• [6] A novel microRNA identified in hepatocellular carcinomas is responsive to LEF1 and facilitates proliferation and epithelial-mesenchymal transition via targeting of NFIX.Oncogenesis. 2018 Feb 23;7(2):22. doi: 10.1038/s41389-017-0010-x.
• [7] Evaluation of serum autoantibodies against tumor-associated antigens as biomarkers in lung cancer.Tumour Biol. 2017 Oct;39(10):1010428317711662. doi: 10.1177/1010428317711662.
• [8] CAPER- alternative splicing regulates the expression of vascular endothelial growth factor?in Ewing sarcoma cells.Cancer. 2012 Apr 15;118(8):2106-16. doi: 10.1002/cncr.26488. Epub 2011 Aug 25.
• [9] Overexpression of HCC1/CAPER may play a role in lung cancer carcinogenesis.Tumour Biol. 2014 Jul;35(7):6311-7. doi: 10.1007/s13277-014-1819-y. Epub 2014 Mar 19.
• [10] An integrated approach in the discovery and characterization of a novel nuclear protein over-expressed in liver and pancreatic tumors.FEBS Lett. 2001 May 11;496(2-3):109-16. doi: 10.1016/s0014-5793(01)02409-7.
• [11] Hypoxia-induced long non-coding RNA DARS-AS1 regulates RBM39 stability to promote myeloma malignancy.Haematologica. 2020 Jun;105(6):1630-1640. doi: 10.3324/haematol.2019.218289. Epub 2019 Jul 9.
• [12] No Matter How You Splice It, RBM39 Inhibition Targets Spliceosome Mutant AML.Cancer Cell. 2019 Mar 18;35(3):337-339. doi: 10.1016/j.ccell.2019.02.013.
• [13] Circular RNAs are differentially expressed in prostate cancer and are potentially associated with resistance to enzalutamide.Sci Rep. 2019 Jul 24;9(1):10739. doi: 10.1038/s41598-019-47189-2.
• [14] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [15] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [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] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [19] A genomic approach to predict synergistic combinations for breast cancer treatment. Pharmacogenomics J. 2013 Feb;13(1):94-104. doi: 10.1038/tpj.2011.48. Epub 2011 Nov 15.
• [20] 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.
• [21] Curcumin downregulates the inflammatory cytokines CXCL1 and -2 in breast cancer cells via NFkappaB. Carcinogenesis. 2008 Apr;29(4):779-89.
• [22] 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.
• [23] 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.
• [24] 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.
• [25] Clarifying off-target effects for torcetrapib using network pharmacology and reverse docking approach. BMC Syst Biol. 2012 Dec 10;6:152.
• [26] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [27] 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.
• [28] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [29] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.
• [30] Global changes in gene regulation demonstrate that unconjugated bilirubin is able to upregulate and activate select components of the endoplasmic reticulum stress response pathway. J Biochem Mol Toxicol. 2010 Mar-Apr;24(2):73-88.