Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU9Z17K)

• DOT Name: Disks large homolog 5 (DLG5)
• Synonyms: Discs large protein P-dlg; Placenta and prostate DLG
• Gene Name: DLG5
• Related Disease:
  Bladder cancer
  Breast cancer
  Breast carcinoma
  Cystic kidney disease
  Hydrocephalus
  Matthew-Wood syndrome
  Pancreatic tumour
  Primary sclerosing cholangitis
  Urinary bladder cancer
  Urinary bladder neoplasm
  Hepatocellular carcinoma
  Neoplasm
  Multiple sclerosis
  Advanced cancer
  Ciliopathy
  Congenital anomaly of kidney and urinary tract
  Prostate cancer
  Prostate carcinoma
• UniProt ID: DLG5_HUMAN
• PDB ID: 1UIT
• Pfam ID: PF16610 ; PF00625 ; PF00595 ; PF04822
• Sequence:
  MEPQRRELLAQCQQSLAQAMTEVEAVLGLLEAAGALSPGERRQLDEEAGGAKAELLLKLL
  LAKERDHFQDLRAALEKTQPHLLPILYLNGVVGPPQPAEGAGSTYSVLSTMPSDSESSSS
  LSSVGTTGKAPSPPPLLTDQQVNEKVENLSIQLRLMTRERNELRKRLAFATHGTAFDKRP
  YHRLNPDYERLKIQCVRAMSDLQSLQNQHTNALKRCEEVAKETDFYHTLHSRLLSDQTRL
  KDDVDMLRRENGQLLRERNLLQQSWEDMKRLHEEDQKEIGDLRAQQQQVLKHNGSSEILN
  KLYDTAMDKLEVVKKDYDALRKRYSEKVAIHNADLSRLEQLGEENQRLLKQTEMLTQQRD
  TAIQLQHQCALSLRRFEAIHHELNKATAQNKDLQWEMELLQSELTELRTTQVKTAKESEK
  YREERDAVYSEYKLIMSERDQVISELDKLQTEVELAESKLKSSTSEKKAANEEMEALRQI
  KDTVTMDAGRANKEVEILRKQCKALCQELKEALQEADVAKCRRDWAFQERDKIVAERDSI
  RTLCDNLRRERDRAVSELAEALRSLDDTRKQKNDVSRELKELKEQMESQLEKEARFRQLM
  AHSSHDSAIDTDSMEWETEVVEFERETEDIDLKALGFDMAEGVNEPCFPGDCGIFVTKVD
  KGSIADGRLRVNDWLLRINDVDLINKDKKQAIKALLNGEGAINMVVRRRKSLGGKVVTPL
  HINLSGQKDSGISLENGVYAAAVLPGSPAAKEGSLAVGDRIVAINGIALDNKSLNECESL
  LRSCQDSLTLSLLKVFPQSSSWSGQNIFENIKDSDKMLSFRAHGPEVQAHNKRNLIQHNN
  STQTDIFYTDRLEDRKEPGPPGGSSSFLHKPFPGGPLQVCPQACPSASERSLSSFRSDAS
  GDRGFGLVDVRGRRPLLPFETEVGPCGVGEASLDKADSEGSNSGGTWPKAMLSSTAVPEK
  LSVYKKPKQRKSIFDPNTFKRPQTPPKIDYLLPGPGPAHSPQPSKRAGPLTPPKPPRRSD
  SIKFQHRLETSSESEATLVGSSPSTSPPSALPPDVDPGEPMHASPPRKARVRIASSYYPE
  GDGDSSHLPAKKSCDEDLTSQKVDELGQKRRRPKSAPSFRPKLAPVVIPAQFLEEQKCVP
  ASGELSPELQEWAPYSPGHSSRHSNPPLYPSRPSVGTVPRSLTPSTTVSSILRNPIYTVR
  SHRVGPCSSPPAARDAGPQGLHPSVQHQGRLSLDLSHRTCSDYSEMRATHGSNSLPSSAR
  LGSSSNLQFKAERIKIPSTPRYPRSVVGSERGSVSHSECSTPPQSPLNIDTLSSCSQSQT
  SASTLPRIAVNPASLGERRKDRPYVEEPRHVKVQKGSEPLGISIVSGEKGGIYVSKVTVG
  SIAHQAGLEYGDQLLEFNGINLRSATEQQARLIIGQQCDTITILAQYNPHVHQLSSHSRS
  SSHLDPAGTHSTLQGSGTTTPEHPSVIDPLMEQDEGPSTPPAKQSSSRIAGDANKKTLEP
  RVVFIKKSQLELGVHLCGGNLHGVFVAEVEDDSPAKGPDGLVPGDLILEYGSLDVRNKTV
  EEVYVEMLKPRDGVRLKVQYRPEEFTKAKGLPGDSFYIRALYDRLADVEQELSFKKDDIL
  YVDDTLPQGTFGSWMAWQLDENAQKIQRGQIPSKYVMDQEFSRRLSMSEVKDDNSATKTL
  SAAARRSFFRRKHKHKRSGSKDGKDLLALDAFSSDSIPLFEDSVSLAYQRVQKVDCTALR
  PVLILGPLLDVVKEMLVNEAPGKFCRCPLEVMKASQQAIERGVKDCLFVDYKRRSGHFDV
  TTVASIKEITEKNRHCLLDIAPHAIERLHHMHIYPIVIFIHYKSAKHIKEQRDPIYLRDK
  VTQRHSKEQFEAAQKLEQEYSRYFTGVIQGGALSSICTQILAMVNQEQNKVLWIPACPL
• Function: Acts as a regulator of the Hippo signaling pathway. Negatively regulates the Hippo signaling pathway by mediating the interaction of MARK3 with STK3/4, bringing them together to promote MARK3-dependent hyperphosphorylation and inactivation of STK3 kinase activity toward LATS1. Positively regulates the Hippo signaling pathway by mediating the interaction of SCRIB with STK4/MST1 and LATS1 which is important for the activation of the Hippo signaling pathway. Involved in regulating cell proliferation, maintenance of epithelial polarity, epithelial-mesenchymal transition (EMT), cell migration and invasion. Plays an important role in dendritic spine formation and synaptogenesis in cortical neurons; regulates synaptogenesis by enhancing the cell surface localization of N-cadherin. Acts as a positive regulator of hedgehog (Hh) signaling pathway. Plays a critical role in the early point of the SMO activity cycle by interacting with SMO at the ciliary base to induce the accumulation of KIF7 and GLI2 at the ciliary tip for GLI2 activation.
• Tissue Specificity: Highly expressed in normal breast tissues and low-grade breast cancer tissues (at protein level) . Highly expressed in the placenta and prostate. Expressed at a lower level in the thyroid, spinal cord, trachea, adrenal gland, skeletal muscle, pancreas, heart, brain, liver and kidney. A short splice product shows more limited expression, being absent from at least the brain.
• KEGG Pathway: Hippo sig.ling pathway (hsa04390)
• Reactome Pathway:
  RHOV GTPase cycle (R-HSA-9013424)
  RND3 GTPase cycle (R-HSA-9696264)
  RND2 GTPase cycle (R-HSA-9696270)
  RND1 GTPase cycle (R-HSA-9696273)
  RHOU GTPase cycle (R-HSA-9013420)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bladder cancer	DISUHNM0	Strong	Altered Expression	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Cystic kidney disease	DISRT1LM	Strong	Biomarker	[3]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[3]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[4]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[4]
Primary sclerosing cholangitis	DISTH5WJ	Strong	Genetic Variation	[5]
Urinary bladder cancer	DISDV4T7	Strong	Altered Expression	[1]
Urinary bladder neoplasm	DIS7HACE	Strong	Posttranslational Modification	[1]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[6]
Neoplasm	DISZKGEW	moderate	Biomarker	[6]
Multiple sclerosis	DISB2WZI	Disputed	Genetic Variation	[7]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[8]
Ciliopathy	DIS10G4I	Limited	Autosomal dominant	[9]
Congenital anomaly of kidney and urinary tract	DIS84IVH	Limited	Autosomal recessive	[10]
Prostate cancer	DISF190Y	Limited	Biomarker	[11]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[11]

4 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 Disks large homolog 5 (DLG5).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Disks large homolog 5 (DLG5).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Disks large homolog 5 (DLG5).	[23]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Disks large homolog 5 (DLG5).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Disks large homolog 5 (DLG5).	[13]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Disks large homolog 5 (DLG5).	[14]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Disks large homolog 5 (DLG5).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Disks large homolog 5 (DLG5).	[16]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Disks large homolog 5 (DLG5).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Disks large homolog 5 (DLG5).	[19]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Disks large homolog 5 (DLG5).	[20]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Disks large homolog 5 (DLG5).	[21]
Promegestone	DMK4S8I	Approved	Promegestone increases the expression of Disks large homolog 5 (DLG5).	[22]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Disks large homolog 5 (DLG5).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Disks large homolog 5 (DLG5).	[24]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Disks large homolog 5 (DLG5).	[25]
[3H]methyltrienolone	DMTSGOW	Investigative	[3H]methyltrienolone increases the expression of Disks large homolog 5 (DLG5).	[26]

References

• [1] Methylation-mediated silencing of Dlg5 facilitates bladder cancer metastasis.Exp Cell Res. 2015 Feb 15;331(2):399-407. doi: 10.1016/j.yexcr.2014.11.015. Epub 2014 Dec 3.
• [2] DLG5 suppresses breast cancer stem cell-like characteristics to restore tamoxifen sensitivity by inhibiting TAZ expression.J Cell Mol Med. 2019 Jan;23(1):512-521. doi: 10.1111/jcmm.13954. Epub 2018 Nov 18.
• [3] Failure of epithelial tube maintenance causes hydrocephalus and renal cysts in Dlg5-/- mice.Dev Cell. 2007 Sep;13(3):338-50. doi: 10.1016/j.devcel.2007.07.017.
• [4] Down-regulation of RAB6KIFL/KIF20A, a kinesin involved with membrane trafficking of discs large homologue 5, can attenuate growth of pancreatic cancer cell.Cancer Res. 2005 Jan 1;65(1):105-12.
• [5] Genetic polymorphisms associated with inflammatory bowel disease do not confer risk for primary sclerosing cholangitis.Am J Gastroenterol. 2007 Jan;102(1):115-21. doi: 10.1111/j.1572-0241.2006.00928.x. Epub 2006 Nov 13.
• [6] -TrCP-mediated ubiquitination and degradation of Dlg5 regulates hepatocellular carcinoma cell proliferation.Cancer Cell Int. 2019 Nov 15;19:298. doi: 10.1186/s12935-019-1029-1. eCollection 2019.
• [7] The role of inflammatory bowel disease susceptibility loci in multiple sclerosis and systemic lupus erythematosus.Genes Immun. 2006 Jun;7(4):327-34. doi: 10.1038/sj.gene.6364303. Epub 2006 Apr 27.
• [8] Novel significant stage-specific differentially expressed genes in hepatocellular carcinoma.BMC Cancer. 2019 Jul 5;19(1):663. doi: 10.1186/s12885-019-5838-3.
• [9] DLG5 variants are associated with multiple congenital anomalies including ciliopathy phenotypes. J Med Genet. 2021 Jul;58(7):453-464. doi: 10.1136/jmedgenet-2019-106805. Epub 2020 Jul 6.
• [10] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [11] Loss of Dlg5 expression promotes the migration and invasion of prostate cancer cells via Girdin phosphorylation.Oncogene. 2015 Feb 26;34(9):1141-9. doi: 10.1038/onc.2014.31. Epub 2014 Mar 24.
• [12] 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.
• [13] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [14] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [15] 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.
• [16] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [17] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [18] 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.
• [19] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [20] Progestins regulate genes that can elicit both proliferative and antiproliferative effects in breast cancer cells. Oncol Rep. 2008 Jun;19(6):1627-34.
• [21] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [22] Short-chain fatty acids enhance nuclear receptor activity through mitogen-activated protein kinase activation and histone deacetylase inhibition. Proc Natl Acad Sci U S A. 2004 May 4;101(18):7199-204.
• [23] 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.
• [24] 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.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [26] Analysis of the prostate cancer cell line LNCaP transcriptome using a sequencing-by-synthesis approach. BMC Genomics. 2006 Sep 29;7:246. doi: 10.1186/1471-2164-7-246.