Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT0DJX74)

• DOT Name: Heterogeneous nuclear ribonucleoprotein L (HNRNPL)
• Synonyms: hnRNP L
• Gene Name: HNRNPL
• Related Disease:
  Adult glioblastoma
  B-cell neoplasm
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Gastric cancer
  Gastric neoplasm
  Glioblastoma multiforme
  Head-neck squamous cell carcinoma
  Hepatitis C virus infection
  Hereditary diffuse gastric adenocarcinoma
  Osteoporosis
  Periodontitis
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Squamous cell carcinoma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Hepatocellular carcinoma
  Childhood kidney Wilms tumor
  Hypoglycemia
  Neoplasm
  Small lymphocytic lymphoma
  Wilms tumor
• UniProt ID: HNRPL_HUMAN
• PDB ID: 3R27; 3TO8; 7EVR
• Pfam ID: PF00076 ; PF13893 ; PF11835
• Sequence:
  MSRRLLPRAEKRRRRLEQRQQPDEQRRRSGAMVKMAAAGGGGGGGRYYGGGSEGGRAPKR
  LKTDNAGDQHGGGGGGGGGAGAAGGGGGGENYDDPHKTPASPVVHIRGLIDGVVEADLVE
  ALQEFGPISYVVVMPKKRQALVEFEDVLGACNAVNYAADNQIYIAGHPAFVNYSTSQKIS
  RPGDSDDSRSVNSVLLFTILNPIYSITTDVLYTICNPCGPVQRIVIFRKNGVQAMVEFDS
  VQSAQRAKASLNGADIYSGCCTLKIEYAKPTRLNVFKNDQDTWDYTNPNLSGQGDPGSNP
  NKRQRQPPLLGDHPAEYGGPHGGYHSHYHDEGYGPPPPHYEGRRMGPPVGGHRRGPSRYG
  PQYGHPPPPPPPPEYGPHADSPVLMVYGLDQSKMNCDRVFNVFCLYGNVEKVKFMKSKPG
  AAMVEMADGYAVDRAITHLNNNFMFGQKLNVCVSKQPAIMPGQSYGLEDGSCSYKDFSES
  RNNRFSTPEQAAKNRIQHPSNVLHFFNAPLEVTEENFFEICDELGVKRPSSVKVFSGKSE
  RSSSGLLEWESKSDALETLGFLNHYQMKNPNGPYPYTLKLCFSTAQHAS
• Function: Splicing factor binding to exonic or intronic sites and acting as either an activator or repressor of exon inclusion. Exhibits a binding preference for CA-rich elements. Component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes and associated with most nascent transcripts. Associates, together with APEX1, to the negative calcium responsive element (nCaRE) B2 of the APEX2 promoter. As part of a ribonucleoprotein complex composed at least of ZNF827, HNRNPK and the circular RNA circZNF827 that nucleates the complex on chromatin, may negatively regulate the transcription of genes involved in neuronal differentiation. Regulates alternative splicing of a core group of genes involved in neuronal differentiation, likely by mediating H3K36me3-coupled transcription elongation and co-transcriptional RNA processing via interaction with CHD8.
• Reactome Pathway:
  Processing of Capped Intron-Containing Pre-mRNA (R-HSA-72203)
  mRNA Splicing - Major Pathway (R-HSA-72163)

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
B-cell neoplasm	DISVY326	Strong	Biomarker	[2]
Bladder cancer	DISUHNM0	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[4]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[5]
Colon cancer	DISVC52G	Strong	Altered Expression	[6]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[7]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Gastric neoplasm	DISOKN4Y	Strong	Biomarker	[8]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[4]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[9]
Hereditary diffuse gastric adenocarcinoma	DISUIBYS	Strong	Biomarker	[8]
Osteoporosis	DISF2JE0	Strong	Biomarker	[10]
Periodontitis	DISI9JOI	Strong	Biomarker	[10]
Prostate cancer	DISF190Y	Strong	Biomarker	[11]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[11]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[12]
Squamous cell carcinoma	DISQVIFL	Strong	Genetic Variation	[4]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[3]
Urinary bladder neoplasm	DIS7HACE	Strong	Altered Expression	[3]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[13]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Biomarker	[14]
Hypoglycemia	DISRCKR7	Limited	Altered Expression	[15]
Neoplasm	DISZKGEW	Limited	Altered Expression	[2]
Small lymphocytic lymphoma	DIS30POX	Limited	Altered Expression	[16]
Wilms tumor	DISB6T16	Limited	Biomarker	[14]

10 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 Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[17]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[21]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[23]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[29]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 decreases the sumoylation of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Heterogeneous nuclear ribonucleoprotein L (HNRNPL).	[26]

References

• [1] Long Noncoding RNA SChLAP1 Forms a Growth-Promoting Complex with HNRNPL in Human Glioblastoma through Stabilization of ACTN4 and Activation of NF-B Signaling.Clin Cancer Res. 2019 Nov 15;25(22):6868-6881. doi: 10.1158/1078-0432.CCR-19-0747. Epub 2019 Sep 6.
• [2] hnRNP L-dependent protection of normal mRNAs from NMD subverts quality control in B cell lymphoma.EMBO J. 2019 Feb 1;38(3):e99128. doi: 10.15252/embj.201899128. Epub 2018 Dec 7.
• [3] HnRNP-L mediates bladder cancer progression by inhibiting apoptotic signaling and enhancing MAPK signaling pathways.Oncotarget. 2017 Feb 21;8(8):13586-13599. doi: 10.18632/oncotarget.14600.
• [4] Inclusion of hnRNP L Alternative Exon 7 Is Associated with Good Prognosis and Inhibited by Oncogene SRSF3 in Head and Neck Squamous Cell Carcinoma.Biomed Res Int. 2019 Nov 13;2019:9612425. doi: 10.1155/2019/9612425. eCollection 2019.
• [5] An integrative approach to identify YB-1-interacting proteins required for cisplatin resistance in MCF7 and MDA-MB-231 breast cancer cells. Cancer Sci. 2011 Jul;102(7):1410-7. doi: 10.1111/j.1349-7006.2011.01948.x. Epub 2011 May 5.
• [6] Interferon regulatory factor 1 and a variant of heterogeneous nuclear ribonucleoprotein L coordinately silence the gene for adhesion protein CEACAM1.J Biol Chem. 2018 Jun 15;293(24):9277-9291. doi: 10.1074/jbc.RA117.001507. Epub 2018 May 2.
• [7] Heterogeneous nuclear ribonucleoprotein L facilitates recruitment of 53BP1 and BRCA1 at the DNA break sites induced by oxaliplatin in colorectal cancer.Cell Death Dis. 2019 Jul 18;10(8):550. doi: 10.1038/s41419-019-1784-x.
• [8] A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.PLoS One. 2011 Feb 18;6(2):e16694. doi: 10.1371/journal.pone.0016694.
• [9] hnRNP L and NF90 interact with hepatitis C virus 5'-terminal untranslated RNA and promote efficient replication.J Virol. 2014 Jul;88(13):7199-209. doi: 10.1128/JVI.00225-14. Epub 2014 Apr 9.
• [10] HnRNPL inhibits the osteogenic differentiation of PDLCs stimulated by SrCl(2) through repressing Setd2.J Cell Mol Med. 2019 Apr;23(4):2667-2677. doi: 10.1111/jcmm.14166. Epub 2019 Feb 12.
• [11] HnRNP-L promotes prostate cancer progression by enhancing cell cycling and inhibiting apoptosis.Oncotarget. 2017 Mar 21;8(12):19342-19353. doi: 10.18632/oncotarget.14258.
• [12] Genome-wide CRISPR screen identifies HNRNPL as a prostate cancer dependency regulating RNA splicing.Proc Natl Acad Sci U S A. 2017 Jun 27;114(26):E5207-E5215. doi: 10.1073/pnas.1617467114. Epub 2017 Jun 13.
• [13] Systematic analysis and prediction model construction of alternative splicing events in hepatocellular carcinoma: a study on the basis of large-scale spliceseq data from The Cancer Genome Atlas.PeerJ. 2019 Dec 9;7:e8245. doi: 10.7717/peerj.8245. eCollection 2019.
• [14] HnRNPL promotes Wilms tumor progression by regulating the p53 and Bcl2 pathways.Onco Targets Ther. 2019 May 29;12:4269-4279. doi: 10.2147/OTT.S203046. eCollection 2019.
• [15] hnRNP A2 and hnRNP L bind the 3'UTR of glucose transporter 1 mRNA and exist as a complex in vivo.Biochem Biophys Res Commun. 1999 Aug 11;261(3):646-51. doi: 10.1006/bbrc.1999.1040.
• [16] HNRNPL Restrains miR-155 Targeting of BUB1 to Stabilize Aberrant Karyotypes of Transformed Cells in Chronic Lymphocytic Leukemia.Cancers (Basel). 2019 Apr 23;11(4):575. doi: 10.3390/cancers11040575.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] 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.
• [19] 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.
• [20] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [21] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [22] 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.
• [23] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [24] 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.
• [25] 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.
• [26] 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.
• [27] 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.
• [28] 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.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.