Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTN1CG6R)

• DOT Name: LIM domain-containing protein 1 (LIMD1)
• Gene Name: LIMD1
• Related Disease:
  Lung adenocarcinoma
  Breast carcinoma
  Breast neoplasm
  Carcinoma of esophagus
  Cervical cancer
  Cervical carcinoma
  Cervical Intraepithelial neoplasia
  Clear cell renal carcinoma
  Esophageal cancer
  Head-neck squamous cell carcinoma
  Human papillomavirus infection
  Lung cancer
  Lung carcinoma
  Lymphoma, non-Hodgkin, familial
  Neoplasm of esophagus
  Non-hodgkin lymphoma
  Renal cell carcinoma
  Lung neoplasm
  Lymphoma
  Advanced cancer
  Gastric cancer
  Neoplasm
  Stomach cancer
• UniProt ID: LIMD1_HUMAN
• Pfam ID: PF00412
• Sequence:
  MDKYDDLGLEASKFIEDLNMYEASKDGLFRVDKGAGNNPEFEETRRVFATKMAKIHLQQQ
  QQQLLQEETLPRGSRGPVNGGGRLGPQARWEVVGSKLTVDGAAKPPLAASTGAPGAVTTL
  AAGQPPYPPQEQRSRPYLHGTRHGSQDCGSRESLATSEMSAFHQPGPCEDPSCLTHGDYY
  DNLSLASPKWGDKPGVSPSIGLSVGSGWPSSPGSDPPLPKPCGDHPLNHRQLSLSSSRSS
  EGSLGGQNSGIGGRSSEKPTGLWSTASSQRVSPGLPSPNLENGAPAVGPVQPRTPSVSAP
  LALSCPRQGGLPRSNSGLGGEVSGVMSKPNVDPQPWFQDGPKSYLSSSAPSSSPAGLDGS
  QQGAVPGLGPKPGCTDLGTGPKLSPTSLVHPVMSTLPELSCKEGPLGWSSDGSLGSVLLD
  SPSSPRVRLPCQPLVPGPELRPSAAELKLEALTQRLEREMDAHPKADYFGACVKCSKGVF
  GAGQACQAMGNLYHDTCFTCAACSRKLRGKAFYFVNGKVFCEEDFLYSGFQQSADRCFLC
  GHLIMDMILQALGKSYHPGCFRCVICNECLDGVPFTVDSENKIYCVRDYHKVLAPKCAAC
  GLPILPPEGSDETIRVVSMDRDYHVECYHCEDCGLELNDEDGHRCYPLEDHLFCHSCHVK
  RLEKRPSSTALHQHHF
• Function: Adapter or scaffold protein which participates in the assembly of numerous protein complexes and is involved in several cellular processes such as cell fate determination, cytoskeletal organization, repression of gene transcription, cell-cell adhesion, cell differentiation, proliferation and migration. Positively regulates microRNA (miRNA)-mediated gene silencing and is essential for P-body formation and integrity. Acts as a hypoxic regulator by bridging an association between the prolyl hydroxylases and VHL enabling efficient degradation of HIF1A. Acts as a transcriptional corepressor for SNAI1- and SNAI2/SLUG-dependent repression of E-cadherin transcription. Negatively regulates the Hippo signaling pathway and antagonizes phosphorylation of YAP1. Inhibits E2F-mediated transcription, and suppresses the expression of the majority of genes with E2F1-responsive elements. Regulates osteoblast development, function, differentiation and stress osteoclastogenesis. Enhances the ability of TRAF6 to activate adapter protein complex 1 (AP-1) and negatively regulates the canonical Wnt receptor signaling pathway in osteoblasts. May act as a tumor suppressor by inhibiting cell proliferation.
• Tissue Specificity: Expressed in normal and breast cancer tissues (at protein level). Ubiquitous.
• KEGG Pathway:
  Hippo sig.ling pathway (hsa04390)
  Hippo sig.ling pathway - multiple species (hsa04392)
• Reactome Pathway: Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha (R-HSA-1234176)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[3]
Carcinoma of esophagus	DISS6G4D	Strong	Biomarker	[4]
Cervical cancer	DISFSHPF	Strong	Biomarker	[5]
Cervical carcinoma	DIST4S00	Strong	Altered Expression	[5]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Genetic Variation	[5]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[6]
Esophageal cancer	DISGB2VN	Strong	Biomarker	[4]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Altered Expression	[7]
Human papillomavirus infection	DISX61LX	Strong	Genetic Variation	[7]
Lung cancer	DISCM4YA	Strong	Biomarker	[8]
Lung carcinoma	DISTR26C	Strong	Biomarker	[8]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	Strong	Biomarker	[9]
Neoplasm of esophagus	DISOLKAQ	Strong	Biomarker	[4]
Non-hodgkin lymphoma	DISS2Y8A	Strong	Biomarker	[9]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[6]
Lung neoplasm	DISVARNB	moderate	Biomarker	[1]
Lymphoma	DISN6V4S	moderate	Altered Expression	[10]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[9]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[11]
Neoplasm	DISZKGEW	Limited	Biomarker	[8]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[11]

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 LIM domain-containing protein 1 (LIMD1).	[12]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of LIM domain-containing protein 1 (LIMD1).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of LIM domain-containing protein 1 (LIMD1).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of LIM domain-containing protein 1 (LIMD1).	[19]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of LIM domain-containing protein 1 (LIMD1).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of LIM domain-containing protein 1 (LIMD1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin increases the expression of LIM domain-containing protein 1 (LIMD1).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of LIM domain-containing protein 1 (LIMD1).	[16]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of LIM domain-containing protein 1 (LIMD1).	[17]

References

• [1] The chromosome 3p21.3-encoded gene, LIMD1, is a critical tumor suppressor involved in human lung cancer development.Proc Natl Acad Sci U S A. 2008 Dec 16;105(50):19932-7. doi: 10.1073/pnas.0805003105. Epub 2008 Dec 5.
• [2] Identification of rare variants in the hLIMD1 gene in breast cancer.Cancer Genet Cytogenet. 2007 Oct 1;178(1):36-41. doi: 10.1016/j.cancergencyto.2007.06.007.
• [3] Cell cycle regulated phosphorylation of LIMD1 in cell lines and expression in human breast cancers.Cancer Lett. 2008 Aug 18;267(1):55-66. doi: 10.1016/j.canlet.2008.03.015. Epub 2008 Apr 24.
• [4] Novel BRCA2-Interacting Protein, LIMD1, Is Essential for the Centrosome Localization of BRCA2 in Esophageal Cancer Cell.Oncol Res. 2016;24(4):247-53. doi: 10.3727/096504016X14652175055765.
• [5] Deregulation of LIMD1-VHL-HIF-1-VEGF pathway is associated with different stages of cervical cancer.Biochem J. 2018 May 31;475(10):1793-1806. doi: 10.1042/BCJ20170649.
• [6] Over expression of HIF1 is associated with inactivation of both LimD1 and VHL in renal cell carcinoma: Clinical importance.Pathol Res Pract. 2017 Dec;213(12):1477-1481. doi: 10.1016/j.prp.2017.10.009. Epub 2017 Oct 10.
• [7] LIMD1 is more frequently altered than RB1 in head and neck squamous cell carcinoma: clinical and prognostic implications.Mol Cancer. 2010 Mar 12;9:58. doi: 10.1186/1476-4598-9-58.
• [8] LIMD1 phosphorylation in mitosis is required for mitotic progression and its tumor-suppressing activity.FEBS J. 2019 Mar;286(5):963-974. doi: 10.1111/febs.14743. Epub 2019 Jan 16.
• [9] Silencing of LIMD1 promotes proliferation and reverses cell adhesion-mediated drug resistance in non-Hodgkin's lymphoma.Oncol Lett. 2019 Mar;17(3):2993-3000. doi: 10.3892/ol.2019.9921. Epub 2019 Jan 11.
• [10] LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death.Oncotarget. 2017 Dec 26;9(5):6282-6297. doi: 10.18632/oncotarget.23676. eCollection 2018 Jan 19.
• [11] LIMD1 is a survival prognostic marker of gastric cancer and hinders tumor progression by suppressing activation of YAP1.Cancer Manag Res. 2018 Oct 9;10:4349-4361. doi: 10.2147/CMAR.S174856. eCollection 2018.
• [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] 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.
• [14] 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.
• [15] 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.
• [16] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [17] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [18] 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.
• [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.