Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ5BAJ9)

• DOT Name: LIM/homeobox protein Lhx3 (LHX3)
• Synonyms: LIM homeobox protein 3
• Gene Name: LHX3
• Related Disease:
  Hepatocellular carcinoma
  Non-acquired combined pituitary hormone deficiency with spine abnormalities
  Atrial fibrillation
  Hypothyroidism
  Lung adenocarcinoma
  Non-small-cell lung cancer
  Obesity
  Pituitary dwarfism
  Sensorineural hearing loss disorder
  Familial atrial fibrillation
  Hypothyroidism due to deficient transcription factors involved in pituitary development or function
  Advanced cancer
  Congenital isolated adrenocorticotropic hormone deficiency
  Pituitary gland disorder
• UniProt ID: LHX3_HUMAN
• Pfam ID: PF00046 ; PF00412
• Sequence:
  MLLETGLERDRARPGAAAVCTLGGTREIPLCAGCDQHILDRFILKALDRHWHSKCLKCSD
  CHTPLAERCFSRGESVYCKDDFFKRFGTKCAACQLGIPPTQVVRRAQDFVYHLHCFACVV
  CKRQLATGDEFYLMEDSRLVCKADYETAKQREAEATAKRPRTTITAKQLETLKSAYNTSP
  KPARHVREQLSSETGLDMRVVQVWFQNRRAKEKRLKKDAGRQRWGQYFRNMKRSRGGSKS
  DKDSVQEGQDSDAEVSFPDEPSLAEMGPANGLYGSLGEPTQALGRPSGALGNFSLEHGGL
  AGPEQYRELRPGSPYGVPPSPAAPQSLPGPQPLLSSLVYPDTSLGLVPSGAPGGPPPMRV
  LAGNGPSSDLSTGSSGGYPDFPASPASWLDEVDHAQF
• Function: Transcription factor. Recognizes and binds to the consensus sequence motif 5'-AATTAATTA-3' in the regulatory elements of target genes, such as glycoprotein hormones alpha chain CGA and visual system homeobox CHX10, positively modulating transcription; transcription can be co-activated by LDB2. Synergistically enhances transcription from the prolactin promoter in cooperation with POU1F1/Pit-1. Required for the establishment of the specialized cells of the pituitary gland and the nervous system. Involved in the development of interneurons and motor neurons in cooperation with LDB1 and ISL1.
• Reactome Pathway: Regulation of expression of SLITs and ROBOs (R-HSA-9010553)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[1]
Non-acquired combined pituitary hormone deficiency with spine abnormalities	DISTD31T	Definitive	Autosomal recessive	[2]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[3]
Hypothyroidism	DISR0H6D	Strong	Genetic Variation	[4]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[5]
Obesity	DIS47Y1K	Strong	Altered Expression	[6]
Pituitary dwarfism	DISI019B	Strong	Biomarker	[7]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Biomarker	[8]
Familial atrial fibrillation	DISL4AGF	moderate	Biomarker	[3]
Hypothyroidism due to deficient transcription factors involved in pituitary development or function	DISCAAEX	Supportive	Autosomal dominant	[9]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[10]
Congenital isolated adrenocorticotropic hormone deficiency	DISYMJJV	Limited	Biomarker	[4]
Pituitary gland disorder	DIS7XB48	Limited	Biomarker	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of LIM/homeobox protein Lhx3 (LHX3).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of LIM/homeobox protein Lhx3 (LHX3).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of LIM/homeobox protein Lhx3 (LHX3).	[13]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of LIM/homeobox protein Lhx3 (LHX3).	[14]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of LIM/homeobox protein Lhx3 (LHX3).	[15]
Liothyronine	DM6IR3P	Approved	Liothyronine decreases the expression of LIM/homeobox protein Lhx3 (LHX3).	[16]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of LIM/homeobox protein Lhx3 (LHX3).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of LIM/homeobox protein Lhx3 (LHX3).	[18]

References

• [1] LHX3 is an advanced-stage prognostic biomarker and metastatic oncogene in hepatocellular carcinoma.Cancer Biomark. 2019;26(1):31-39. doi: 10.3233/CBM-182257.
• [2] Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet. 2000 Jun;25(2):182-6. doi: 10.1038/76041.
• [3] Multi-ethnic genome-wide association study for atrial fibrillation.Nat Genet. 2018 Jun 11;50(9):1225-1233. doi: 10.1038/s41588-018-0133-9.
• [4] A novel mutation of LHX3 is associated with combined pituitary hormone deficiency including ACTH deficiency, sensorineural hearing loss, and short neck-a case report and review of the literature.Eur J Pediatr. 2011 Aug;170(8):1017-21. doi: 10.1007/s00431-011-1393-x. Epub 2011 Jan 20.
• [5] LHX3 is an early stage and radiosensitivity prognostic biomarker in lung adenocarcinoma.Oncol Rep. 2017 Sep;38(3):1482-1490. doi: 10.3892/or.2017.5833. Epub 2017 Jul 18.
• [6] Hypogonadotropic hypogonadism.Semin Reprod Med. 2002 Nov;20(4):327-38. doi: 10.1055/s-2002-36707.
• [7] Molecular screening of a large cohort of Moroccan patients with congenital hypopituitarism.Clin Endocrinol (Oxf). 2015 Jun;82(6):876-84. doi: 10.1111/cen.12706. Epub 2015 Feb 6.
• [8] Two novel LHX3 mutations in patients with combined pituitary hormone deficiency including cervical rigidity and sensorineural hearing loss.BMC Endocr Disord. 2017 Mar 16;17(1):17. doi: 10.1186/s12902-017-0164-8.
• [9] Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17. doi: 10.1186/1750-1172-5-17.
• [10] Lhx3 is required to maintain cancer cell development of high-grade oligodendroglioma.Mol Cell Biochem. 2015 Jan;399(1-2):1-5. doi: 10.1007/s11010-014-2209-x. Epub 2014 Nov 16.
• [11] 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.
• [12] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] 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.
• [15] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [16] Monitoring of deiodinase deficiency based on transcriptomic responses in SH-SY5Y cells. Arch Toxicol. 2013 Jun;87(6):1103-13. doi: 10.1007/s00204-013-1018-4. Epub 2013 Feb 10.
• [17] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [18] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.