Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXCN9CG)

• DOT Name: Poly(rC)-binding protein 2 (PCBP2)
• Synonyms: Alpha-CP2; Heterogeneous nuclear ribonucleoprotein E2; hnRNP E2
• Gene Name: PCBP2
• Related Disease:
  Blast phase chronic myelogenous leukemia, BCR-ABL1 positive
  Carcinoma
  Chronic obstructive pulmonary disease
  Esophageal squamous cell carcinoma
  Hepatitis C virus infection
  Hepatocellular carcinoma
  Idiopathic interstitial pneumonia
  Malignant glioma
  Metastatic prostate carcinoma
  Oral cancer
  Pick disease
  Prostate neoplasm
  Respiratory disease
  Semantic dementia
  Squamous cell carcinoma
  Stomach cancer
  Adult glioblastoma
  Bladder cancer
  Clear cell renal carcinoma
  Glioblastoma multiforme
  Renal cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Rabies
  Glioma
  Matthew-Wood syndrome
  Neoplasm
  Pancreatic ductal carcinoma
• UniProt ID: PCBP2_HUMAN
• PDB ID: 2AXY; 2JZX; 2P2R; 2PQU; 2PY9
• Pfam ID: PF00013
• Sequence:
  MDTGVIEGGLNVTLTIRLLMHGKEVGSIIGKKGESVKKMREESGARINISEGNCPERIIT
  LAGPTNAIFKAFAMIIDKLEEDISSSMTNSTAASRPPVTLRLVVPASQCGSLIGKGGCKI
  KEIRESTGAQVQVAGDMLPNSTERAITIAGIPQSIIECVKQICVVMLETLSQSPPKGVTI
  PYRPKPSSSPVIFAGGQDRYSTGSDSASFPHTTPSMCLNPDLEGPPLEAYTIQGQYAIPQ
  PDLTKLHQLAMQQSHFPMTHGNTGFSGIESSSPEVKGYWGLDASAQTTSHELTIPNDLIG
  CIIGRQGAKINEIRQMSGAQIKIANPVEGSTDRQVTITGSAASISLAQYLINVRLSSETG
  GMGSS
• Function: Single-stranded nucleic acid binding protein that binds preferentially to oligo dC. Major cellular poly(rC)-binding protein. Binds also poly(rU). Acts as a negative regulator of antiviral signaling. Negatively regulates cellular antiviral responses mediated by MAVS signaling. It acts as an adapter between MAVS and the E3 ubiquitin ligase ITCH, therefore triggering MAVS ubiquitination and degradation. Negativeley regulates the cGAS-STING pathway via interaction with CGAS, preventing the formation of liquid-like droplets in which CGAS is activated. Together with PCBP1, required for erythropoiesis, possibly by regulating mRNA splicing; (Microbial infection) In case of infection by poliovirus, binds to the viral internal ribosome entry site (IRES) and stimulates the IRES-mediated translation. Also plays a role in initiation of viral RNA replication in concert with the viral protein 3CD.
• Tissue Specificity: Detected in all tissues examined.
• KEGG Pathway: Ferroptosis (hsa04216)
• Reactome Pathway:
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Blast phase chronic myelogenous leukemia, BCR-ABL1 positive	DIS3KLUX	Strong	Biomarker	[1]
Carcinoma	DISH9F1N	Strong	Altered Expression	[2]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Altered Expression	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[5]
Idiopathic interstitial pneumonia	DISH7LPY	Strong	Altered Expression	[3]
Malignant glioma	DISFXKOV	Strong	Biomarker	[6]
Metastatic prostate carcinoma	DISVBEZ9	Strong	Altered Expression	[7]
Oral cancer	DISLD42D	Strong	Altered Expression	[8]
Pick disease	DISP6X50	Strong	Biomarker	[9]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[7]
Respiratory disease	DISGGAGJ	Strong	Altered Expression	[3]
Semantic dementia	DISA7775	Strong	Biomarker	[10]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[8]
Stomach cancer	DISKIJSX	Strong	Biomarker	[11]
Adult glioblastoma	DISVP4LU	moderate	Biomarker	[12]
Bladder cancer	DISUHNM0	moderate	Biomarker	[13]
Clear cell renal carcinoma	DISBXRFJ	moderate	Genetic Variation	[14]
Glioblastoma multiforme	DISK8246	moderate	Biomarker	[12]
Renal cell carcinoma	DISQZ2X8	moderate	Genetic Variation	[14]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[13]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[13]
Rabies	DISSC4V5	Disputed	Biomarker	[15]
Glioma	DIS5RPEH	Limited	Altered Expression	[16]
Matthew-Wood syndrome	DISA7HR7	Limited	Altered Expression	[17]
Neoplasm	DISZKGEW	Limited	Biomarker	[16]
Pancreatic ductal carcinoma	DIS26F9Q	Limited	Altered Expression	[17]

19 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 Poly(rC)-binding protein 2 (PCBP2).	[18]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Poly(rC)-binding protein 2 (PCBP2).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Poly(rC)-binding protein 2 (PCBP2).	[20]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Poly(rC)-binding protein 2 (PCBP2).	[21]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Poly(rC)-binding protein 2 (PCBP2).	[23]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Poly(rC)-binding protein 2 (PCBP2).	[24]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Poly(rC)-binding protein 2 (PCBP2).	[25]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Poly(rC)-binding protein 2 (PCBP2).	[26]
Benzatropine	DMF7EXL	Approved	Benzatropine decreases the expression of Poly(rC)-binding protein 2 (PCBP2).	[27]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Poly(rC)-binding protein 2 (PCBP2).	[28]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Poly(rC)-binding protein 2 (PCBP2).	[29]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Poly(rC)-binding protein 2 (PCBP2).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Poly(rC)-binding protein 2 (PCBP2).	[31]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Poly(rC)-binding protein 2 (PCBP2).	[33]
UNC0379	DMD1E4J	Preclinical	UNC0379 decreases the expression of Poly(rC)-binding protein 2 (PCBP2).	[34]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Poly(rC)-binding protein 2 (PCBP2).	[35]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Poly(rC)-binding protein 2 (PCBP2).	[36]
methyl p-hydroxybenzoate	DMO58UW	Investigative	methyl p-hydroxybenzoate increases the expression of Poly(rC)-binding protein 2 (PCBP2).	[37]
AHPN	DM8G6O4	Investigative	AHPN decreases the expression of Poly(rC)-binding protein 2 (PCBP2).	[38]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Poly(rC)-binding protein 2 (PCBP2).	[22]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Poly(rC)-binding protein 2 (PCBP2).	[32]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Poly(rC)-binding protein 2 (PCBP2).	[32]

References

• [1] miR-328 functions as an RNA decoy to modulate hnRNP E2 regulation of mRNA translation in leukemic blasts.Cell. 2010 Mar 5;140(5):652-65. doi: 10.1016/j.cell.2010.01.007.
• [2] Poly (C)-binding protein 2 (PCBP2) promotes the progression of esophageal squamous cell carcinoma (ESCC) through regulating cellular proliferation and apoptosis.Pathol Res Pract. 2016 Aug;212(8):717-25. doi: 10.1016/j.prp.2016.05.008. Epub 2016 May 27.
• [3] Expression Profile of Six RNA-Binding Proteins in Pulmonary Sarcoidosis.PLoS One. 2016 Aug 30;11(8):e0161669. doi: 10.1371/journal.pone.0161669. eCollection 2016.
• [4] NLRX1 Mediates MAVS Degradation To Attenuate the Hepatitis C Virus-Induced Innate Immune Response through PCBP2.J Virol. 2017 Nov 14;91(23):e01264-17. doi: 10.1128/JVI.01264-17. Print 2017 Dec 1.
• [5] Overexpression of PCBP2 contributes to poor prognosis and enhanced cell growth in human hepatocellular carcinoma.Oncol Rep. 2016 Dec;36(6):3456-3464. doi: 10.3892/or.2016.5167. Epub 2016 Oct 13.
• [6] Interplay between PCBP2 and miRNA modulates ARHGDIA expression and function in glioma migration and invasion.Oncotarget. 2016 Apr 12;7(15):19483-98. doi: 10.18632/oncotarget.6869.
• [7] Selection and cloning of poly(rC)-binding protein 2 and Raf kinase inhibitor protein RNA activators of 2',5'-oligoadenylate synthetase from prostate cancer cells.Nucleic Acids Res. 2006;34(22):6684-95. doi: 10.1093/nar/gkl968. Epub 2006 Dec 1.
• [8] HnRNP E2 is downregulated in human oral cancer cells and the overexpression of hnRNP E2 induces apoptosis.Mol Carcinog. 2007 Mar;46(3):198-207. doi: 10.1002/mc.20265.
• [9] An SRp75/hnRNPG complex interacting with hnRNPE2 regulates the 5' splice site of tau exon 10, whose misregulation causes frontotemporal dementia.Gene. 2011 Oct 10;485(2):130-8. doi: 10.1016/j.gene.2011.06.020. Epub 2011 Jun 30.
• [10] Heterogeneous ribonuclear protein E2 (hnRNP E2) is associated with TDP-43-immunoreactive neurites in Semantic Dementia but not with other TDP-43 pathological subtypes of Frontotemporal Lobar Degeneration.Acta Neuropathol Commun. 2017 Jun 30;5(1):54. doi: 10.1186/s40478-017-0454-4.
• [11] The RNA-binding protein PCBP2 facilitates gastric carcinoma growth by targeting miR-34a.Biochem Biophys Res Commun. 2014 Jun 13;448(4):437-42. doi: 10.1016/j.bbrc.2014.04.124. Epub 2014 May 2.
• [12] High expression of PCBP2 is associated with progression and poor prognosis in patients with glioblastoma.Biomed Pharmacother. 2017 Oct;94:659-665. doi: 10.1016/j.biopha.2017.07.103. Epub 2017 Aug 5.
• [13] KCNQ1OT1 aggravates cell proliferation and migration in bladder cancer through modulating miR-145-5p/PCBP2 axis.Cancer Cell Int. 2019 Dec 3;19:325. doi: 10.1186/s12935-019-1039-z. eCollection 2019.
• [14] A General Framework for Interrogation of mRNA Stability Programs Identifies RNA-Binding Proteins that Govern Cancer Transcriptomes.Cell Rep. 2018 May 8;23(6):1639-1650. doi: 10.1016/j.celrep.2018.04.031.
• [15] The 3' untranslated region of the rabies virus glycoprotein mRNA specifically interacts with cellular PCBP2 protein and promotes transcript stability.PLoS One. 2012;7(3):e33561. doi: 10.1371/journal.pone.0033561. Epub 2012 Mar 16.
• [16] PCBP2 promotes the development of glioma by regulating FHL3/TGF-/Smad signaling pathway.J Cell Physiol. 2020 Apr;235(4):3280-3291. doi: 10.1002/jcp.29104. Epub 2019 Nov 6.
• [17] 2-adrenergic receptor signaling promotes pancreatic ductal adenocarcinoma (PDAC) progression through facilitating PCBP2-dependent c-myc expression.Cancer Lett. 2016 Apr 1;373(1):67-76. doi: 10.1016/j.canlet.2016.01.026. Epub 2016 Jan 21.
• [18] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [19] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] 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.
• [24] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [25] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [26] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [27] 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.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [30] Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discov. 2013 Mar;3(3):308-23.
• [31] 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.
• [32] 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.
• [33] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [34] Epigenetic siRNA and chemical screens identify SETD8 inhibition as a therapeutic strategy for p53 activation in high-risk neuroblastoma. Cancer Cell. 2017 Jan 9;31(1):50-63.
• [35] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [36] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [37] 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.
• [38] ST1926, a novel and orally active retinoid-related molecule inducing apoptosis in myeloid leukemia cells: modulation of intracellular calcium homeostasis. Blood. 2004 Jan 1;103(1):194-207.