Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5NDCT9)

• DOT Name: LIM domain transcription factor LMO4 (LMO4)
• Synonyms: Breast tumor autoantigen; LIM domain only protein 4; LMO-4
• Gene Name: LMO4
• Related Disease:
  Gastric cancer
  HER2/NEU overexpressing breast cancer
  Neuroblastoma
  Stomach cancer
  Advanced cancer
  Alzheimer disease
  Anal intraepithelial neoplasia
  Anencephaly
  Breast cancer
  Breast carcinoma
  Burkitt lymphoma
  Epithelial neoplasm
  Invasive ductal breast carcinoma
  Metastatic malignant neoplasm
  Neoplasm
  Pancreatic cancer
  Pancreatic tumour
  Psoriasis
  Rhabdomyosarcoma
  Squamous cell carcinoma
  T-cell lymphoma
  Thyroid gland papillary carcinoma
  Meningioma
  Hereditary breast carcinoma
  T-cell acute lymphoblastic leukaemia
• UniProt ID: LMO4_HUMAN
• Pfam ID: PF00412
• Sequence:
  MVNPGSSSQPPPVTAGSLSWKRCAGCGGKIADRFLLYAMDSYWHSRCLKCSCCQAQLGDI
  GTSCYTKSGMILCRNDYIRLFGNSGACSACGQSIPASELVMRAQGNVYHLKCFTCSTCRN
  RLVPGDRFHYINGSLFCEHDRPTALINGHLNSLQSNPLLPDQKVC
• Function: Transcription cofactor. Plays a role in establishing motor neuron identity, in concert with MNX1, acting, at least in part, to disrupt LDB1-LHX3 complexes thereby negatively modulating interneuron genes in motor neurons.

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gastric cancer	DISXGOUK	Definitive	Biomarker	[1]
HER2/NEU overexpressing breast cancer	DISYKID5	Definitive	Biomarker	[2]
Neuroblastoma	DISVZBI4	Definitive	Altered Expression	[3]
Stomach cancer	DISKIJSX	Definitive	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[5]
Anal intraepithelial neoplasia	DISJ0JW3	Strong	Biomarker	[6]
Anencephaly	DISIYW6T	Strong	Biomarker	[7]
Breast cancer	DIS7DPX1	Strong	Biomarker	[8]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[8]
Burkitt lymphoma	DIS9D5XU	Strong	Altered Expression	[9]
Epithelial neoplasm	DIS0T594	Strong	Altered Expression	[10]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[11]
Metastatic malignant neoplasm	DIS86UK6	Strong	Altered Expression	[12]
Neoplasm	DISZKGEW	Strong	Altered Expression	[2]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[11]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[11]
Psoriasis	DIS59VMN	Strong	Biomarker	[13]
Rhabdomyosarcoma	DISNR7MS	Strong	Biomarker	[12]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[14]
T-cell lymphoma	DISSXRTQ	Strong	Altered Expression	[13]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[15]
Meningioma	DISPT4TG	moderate	Biomarker	[16]
Hereditary breast carcinoma	DISAEZT5	Limited	Biomarker	[17]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Limited	Biomarker	[18]

2 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 transcription factor LMO4 (LMO4).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of LIM domain transcription factor LMO4 (LMO4).	[30]

17 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 LIM domain transcription factor LMO4 (LMO4).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of LIM domain transcription factor LMO4 (LMO4).	[21]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of LIM domain transcription factor LMO4 (LMO4).	[22]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of LIM domain transcription factor LMO4 (LMO4).	[23]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of LIM domain transcription factor LMO4 (LMO4).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of LIM domain transcription factor LMO4 (LMO4).	[25]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of LIM domain transcription factor LMO4 (LMO4).	[26]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of LIM domain transcription factor LMO4 (LMO4).	[27]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of LIM domain transcription factor LMO4 (LMO4).	[28]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of LIM domain transcription factor LMO4 (LMO4).	[29]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of LIM domain transcription factor LMO4 (LMO4).	[31]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of LIM domain transcription factor LMO4 (LMO4).	[32]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of LIM domain transcription factor LMO4 (LMO4).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of LIM domain transcription factor LMO4 (LMO4).	[34]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of LIM domain transcription factor LMO4 (LMO4).	[35]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of LIM domain transcription factor LMO4 (LMO4).	[36]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of LIM domain transcription factor LMO4 (LMO4).	[37]

References

• [1] LMO4 promotes the invasion and proliferation of gastric cancer by activating PI3K-Akt-mTOR signaling.Am J Transl Res. 2019 Oct 15;11(10):6534-6543. eCollection 2019.
• [2] LMO4 mediates trastuzumab resistance in HER2 positive breast cancer cells.Am J Cancer Res. 2018 Apr 1;8(4):594-609. eCollection 2018.
• [3] LMO4 is an essential cofactor in the Snail2-mediated epithelial-to-mesenchymal transition of neuroblastoma and neural crest cells.J Neurosci. 2013 Feb 13;33(7):2773-83. doi: 10.1523/JNEUROSCI.4511-12.2013.
• [4] Integrative genomics identifies LMO1 as a neuroblastoma oncogene.Nature. 2011 Jan 13;469(7329):216-20. doi: 10.1038/nature09609. Epub 2010 Dec 1.
• [5] Postsynaptic density protein PSD-95 expression in Alzheimer's disease and okadaic acid induced neuritic retraction.Neurobiol Dis. 2008 Jun;30(3):408-419. doi: 10.1016/j.nbd.2008.02.012. Epub 2008 Mar 12.
• [6] Overexpression of LMO4 induces mammary hyperplasia, promotes cell invasion, and is a predictor of poor outcome in breast cancer.Proc Natl Acad Sci U S A. 2005 May 24;102(21):7659-64. doi: 10.1073/pnas.0502990102. Epub 2005 May 16.
• [7] The Grainyhead-like epithelial transactivator Get-1/Grhl3 regulates epidermal terminal differentiation and interacts functionally with LMO4.Dev Biol. 2006 Nov 1;299(1):122-36. doi: 10.1016/j.ydbio.2006.07.015. Epub 2006 Jul 21.
• [8] Comprehensive epigenetic analyses reveal master regulators driving lung metastasis of breast cancer.J Cell Mol Med. 2019 Aug;23(8):5415-5431. doi: 10.1111/jcmm.14424. Epub 2019 Jun 19.
• [9] miR-150 might inhibit cell proliferation and promote cell apoptosis by targeting LMO4 in Burkitt lymphoma.J Cell Physiol. 2019 Jun;234(6):9652-9662. doi: 10.1002/jcp.27652. Epub 2018 Nov 13.
• [10] LMO4 is an essential mediator of ErbB2/HER2/Neu-induced breast cancer cell cycle progression.Oncogene. 2009 Oct 15;28(41):3608-18. doi: 10.1038/onc.2009.221. Epub 2009 Aug 3.
• [11] LIM only 4 is overexpressed in late stage pancreas cancer.Mol Cancer. 2008 Dec 22;7:93. doi: 10.1186/1476-4598-7-93.
• [12] Differential expression of invasion promoting genes in childhood rhabdomyosarcoma.Int J Oncol. 2011 Apr;38(4):993-1000. doi: 10.3892/ijo.2011.921. Epub 2011 Jan 24.
• [13] LMO4 Is a Disease-Provocative Transcription Coregulator Activated by IL-23 in Psoriatic Keratinocytes.J Invest Dermatol. 2018 May;138(5):1078-1087. doi: 10.1016/j.jid.2017.12.010. Epub 2017 Dec 16.
• [14] The LIM-only protein, LMO4, and the LIM domain-binding protein, LDB1, expression in squamous cell carcinomas of the oral cavity.Br J Cancer. 2003 May 19;88(10):1543-8. doi: 10.1038/sj.bjc.6600952.
• [15] Circular RNA circBACH2 plays a role in papillary thyroid carcinoma by sponging miR-139-5p and regulating LMO4 expression.Cell Death Dis. 2019 Feb 22;10(3):184. doi: 10.1038/s41419-019-1439-y.
• [16] Genetic alterations associated with progression and recurrence in meningiomas.J Neuropathol Exp Neurol. 2012 Oct;71(10):882-93. doi: 10.1097/NEN.0b013e31826bf704.
• [17] Mutation analysis of FANCD2, BRIP1/BACH1, LMO4 and SFN in familial breast cancer.Breast Cancer Res. 2005;7(6):R1005-16. doi: 10.1186/bcr1336. Epub 2005 Oct 21.
• [18] The LIM domain gene LMO4 inhibits differentiation of mammary epithelial cells in vitro and is overexpressed in breast cancer.Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14452-7. doi: 10.1073/pnas.251547698.
• [19] 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.
• [20] 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.
• [21] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [22] 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.
• [23] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [24] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [25] 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.
• [26] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [27] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [28] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [29] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [30] 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.
• [31] In Silico Analysis Guides Selection of BET Inhibitors for Triple-Negative Breast Cancer Treatment. Mol Cancer Ther. 2016 Aug;15(8):1823-33. doi: 10.1158/1535-7163.MCT-16-0004. Epub 2016 Jun 2.
• [32] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [33] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [34] 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.
• [35] 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.
• [36] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [37] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.