Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTK61NP8)

• DOT Name: LIM/homeobox protein Lhx2 (LHX2)
• Synonyms: Homeobox protein LH-2; LIM homeobox protein 2
• Gene Name: LHX2
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Anemia
  Bone osteosarcoma
  Liver cirrhosis
  Neoplasm
  Non-small-cell lung cancer
  Osteoarthritis
  Osteosarcoma
  Pituitary gland disorder
  Rheumatoid arthritis
  T-cell acute lymphoblastic leukaemia
  Teratoma
  Carcinoma
  Pancreatic ductal carcinoma
  Patent ductus arteriosus
  Autism
  Breast cancer
  Breast carcinoma
  Insulinoma
  Nasopharyngeal carcinoma
  Neurodevelopmental disorder
  Post-traumatic stress disorder
  Schizophrenia
• UniProt ID: LHX2_HUMAN
• Pfam ID: PF00046 ; PF00412
• Sequence:
  MLFHSLSGPEVHGVIDEMDRRAKSEAPAISSAIDRGDTETTMPSISSDRAALCAGCGGKI
  SDRYYLLAVDKQWHMRCLKCCECKLNLESELTCFSKDGSIYCKEDYYRRFSVQRCARCHL
  GISASEMVMRARDLVYHLNCFTCTTCNKMLTTGDHFGMKDSLVYCRLHFEALLQGEYPAH
  FNHADVAAAAAAAAAAKSAGLGAAGANPLGLPYYNGVGTVQKGRPRKRKSPGPGADLAAY
  NAALSCNENDAEHLDRDQPYPSSQKTKRMRTSFKHHQLRTMKSYFAINHNPDAKDLKQLA
  QKTGLTKRVLQVWFQNARAKFRRNLLRQENTGVDKSTDAALQTGTPSGPASELSNASLSP
  SSTPTTLTDLTSPTLPTVTSVLTSVPGNLEGHEPHSPSQTTLTNLF
• Function: Acts as a transcriptional activator. Stimulates the promoter of the alpha-glycoprotein gene. Transcriptional regulatory protein involved in the control of cell differentiation in developing lymphoid and neural cell types.
• Reactome Pathway:
  Expression and translocation of olfactory receptors (R-HSA-9752946)
  Regulation of expression of SLITs and ROBOs (R-HSA-9010553)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Anemia	DISTVL0C	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[1]
Liver cirrhosis	DIS4G1GX	Strong	Altered Expression	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[6]
Osteoarthritis	DIS05URM	Strong	Altered Expression	[7]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[1]
Pituitary gland disorder	DIS7XB48	Strong	Genetic Variation	[3]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[7]
T-cell acute lymphoblastic leukaemia	DIS17AI2	Strong	Altered Expression	[8]
Teratoma	DIS6ICY4	Strong	Biomarker	[9]
Carcinoma	DISH9F1N	moderate	Altered Expression	[10]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Biomarker	[11]
Patent ductus arteriosus	DIS9P8YS	moderate	Altered Expression	[11]
Autism	DISV4V1Z	Limited	Biomarker	[12]
Breast cancer	DIS7DPX1	Limited	Biomarker	[5]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[5]
Insulinoma	DISIU1JS	Limited	Biomarker	[5]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Biomarker	[13]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[12]
Post-traumatic stress disorder	DISHL1EY	Limited	Genetic Variation	[14]
Schizophrenia	DISSRV2N	Limited	Biomarker	[12]

20 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 LIM/homeobox protein Lhx2 (LHX2).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of LIM/homeobox protein Lhx2 (LHX2).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of LIM/homeobox protein Lhx2 (LHX2).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[20]
Etoposide	DMNH3PG	Approved	Etoposide decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[18]
Mitomycin	DMH0ZJE	Approved	Mitomycin decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[18]
Colchicine	DM2POTE	Approved	Colchicine decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[18]
Hydroxyurea	DMOQVU9	Approved	Hydroxyurea decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[18]
Adenine	DMZLHKJ	Approved	Adenine decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[21]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of LIM/homeobox protein Lhx2 (LHX2).	[22]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of LIM/homeobox protein Lhx2 (LHX2).	[23]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[25]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of LIM/homeobox protein Lhx2 (LHX2).	[26]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of LIM/homeobox protein Lhx2 (LHX2).	[27]

References

• [1] LHX2 promotes malignancy and inhibits autophagy via mTOR in osteosarcoma and is negatively regulated by miR-129-5p.Aging (Albany NY). 2019 Nov 13;11(21):9794-9810. doi: 10.18632/aging.102427. Epub 2019 Nov 13.
• [2] The Role of Methylated Circulating Nucleic Acids as a Potential Biomarker in Alzheimer's Disease.Mol Neurobiol. 2019 Apr;56(4):2440-2449. doi: 10.1007/s12035-018-1229-z. Epub 2018 Jul 21.
• [3] Screening of LHX2 in patients presenting growth retardation with posterior pituitary and ocular abnormalities.Eur J Endocrinol. 2012 Jul;167(1):85-91. doi: 10.1530/EJE-12-0026. Epub 2012 Apr 24.
• [4] Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis.Am J Physiol Gastrointest Liver Physiol. 2009 Dec;297(6):G1093-106. doi: 10.1152/ajpgi.00292.2009. Epub 2009 Oct 8.
• [5] LIM-homeobox gene 2 promotes tumor growth and metastasis by inducing autocrine and paracrine PDGF-B signaling.Mol Oncol. 2014 Mar;8(2):401-16. doi: 10.1016/j.molonc.2013.12.009. Epub 2013 Dec 25.
• [6] Inhibition of LHX2 by miR-124 suppresses cellular migration and invasion in non-small cell lung cancer.Oncol Lett. 2017 Sep;14(3):3429-3436. doi: 10.3892/ol.2017.6607. Epub 2017 Jul 18.
• [7] Distinctive gene expression signatures in rheumatoid arthritis synovial tissue fibroblast cells: correlates with disease activity.Genes Immun. 2007 Sep;8(6):480-91. doi: 10.1038/sj.gene.6364400. Epub 2007 Jun 14.
• [8] Overexpression of Lhx2 suppresses proliferation of human T cell acute lymphoblastic leukemia-derived cells, partly by reducing LMO2 protein levels.Biochem Biophys Res Commun. 2018 Jan 15;495(3):2310-2316. doi: 10.1016/j.bbrc.2017.12.135. Epub 2017 Dec 24.
• [9] OP9-Lhx2 stromal cells facilitate derivation of hematopoietic progenitors both in vitro and in vivo.Stem Cell Res. 2015 Sep;15(2):395-402. doi: 10.1016/j.scr.2015.08.009. Epub 2015 Aug 21.
• [10] Magnifying glass on spiradenoma and cylindroma histogenesis and tumorigenesis using systematic transcriptome analysis.Ann Diagn Pathol. 2019 Aug;41:14-23. doi: 10.1016/j.anndiagpath.2019.04.015. Epub 2019 May 5.
• [11] Oncogenicity of LHX2 in pancreatic ductal adenocarcinoma.Mol Biol Rep. 2014 Dec;41(12):8163-7. doi: 10.1007/s11033-014-3716-2. Epub 2014 Oct 17.
• [12] Cux2 expression regulated by Lhx2 in the upper layer neurons of the developing cortex.Biochem Biophys Res Commun. 2020 Jan 22;521(4):874-879. doi: 10.1016/j.bbrc.2019.11.004. Epub 2019 Nov 8.
• [13] MicroRNA-506 inhibits tumor growth and metastasis in nasopharyngeal carcinoma through the inactivation of the Wnt/-catenin signaling pathway by down-regulating LHX2.J Exp Clin Cancer Res. 2019 Feb 21;38(1):97. doi: 10.1186/s13046-019-1023-4.
• [14] Genomic predictors of combat stress vulnerability and resilience in U.S. Marines: A genome-wide association study across multiple ancestries implicates PRTFDC1 as a potential PTSD gene.Psychoneuroendocrinology. 2015 Jan;51:459-71. doi: 10.1016/j.psyneuen.2014.10.017. Epub 2014 Oct 30.
• [15] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [16] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Utilization of CDKN1A/p21 gene for class discrimination of DNA damage-induced clastogenicity. Toxicology. 2014 Jan 6;315:8-16. doi: 10.1016/j.tox.2013.10.009. Epub 2013 Nov 6.
• [19] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [20] 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.
• [21] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [22] Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Mar 1;70(15):1821-39.
• [23] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [24] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [25] 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.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [27] 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.