Details of Drug Off-Target (DOT)

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

• DOT Name: Short stature homeobox protein 2 (SHOX2)
• Synonyms: Homeobox protein Og12X; Paired-related homeobox protein SHOT
• Gene Name: SHOX2
• Related Disease:
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Esophageal squamous cell carcinoma
  Estrogen-receptor positive breast cancer
  Familial adenomatous polyposis
  Glioma
  Hepatocellular carcinoma
  Intervertebral disc degeneration
  Leri-Weill dyschondrosteosis
  Neoplasm
  Non-small-cell lung cancer
  Renal cell carcinoma
  Cornelia de Lange syndrome
  Prostate cancer
  Prostate carcinoma
  Advanced cancer
  Arrhythmia
  Lung cancer
  Lung carcinoma
  Pulmonary disease
  Schizophrenia
• UniProt ID: SHOX2_HUMAN
• Pfam ID: PF00046 ; PF03826
• Sequence:
  MEELTAFVSKSFDQKVKEKKEAITYREVLESGPLRGAKEPTGCTEAGRDDRSSPAVRAAG
  GGGGGGGGGGGGGGGGGVGGGGAGGGAGGGRSPVRELDMGAAERSREPGSPRLTEVSPEL
  KDRKEDAKGMEDEGQTKIKQRRSRTNFTLEQLNELERLFDETHYPDAFMREELSQRLGLS
  EARVQVWFQNRRAKCRKQENQLHKGVLIGAASQFEACRVAPYVNVGALRMPFQQDSHCNV
  TPLSFQVQAQLQLDSAVAHAHHHLHPHLAAHAPYMMFPAPPFGLPLATLAADSASAASVV
  AAAAAAKTTSKNSSIADLRLKAKKHAAALGL
• Function: May be a growth regulator and have a role in specifying neural systems involved in processing somatosensory information, as well as in face and body structure formation.
• Tissue Specificity: Expressed in heart, skeletal muscle, liver, lung, bone marrow fibroblast, pancreas and placenta.

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[3]
Estrogen-receptor positive breast cancer	DIS1H502	Strong	Altered Expression	[2]
Familial adenomatous polyposis	DISW53RE	Strong	Genetic Variation	[4]
Glioma	DIS5RPEH	Strong	Altered Expression	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[6]
Intervertebral disc degeneration	DISG3AIM	Strong	Biomarker	[7]
Leri-Weill dyschondrosteosis	DISDPMVZ	Strong	Genetic Variation	[8]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Biomarker	[9]
Renal cell carcinoma	DISQZ2X8	Strong	Altered Expression	[10]
Cornelia de Lange syndrome	DISEQSXO	moderate	Biomarker	[11]
Prostate cancer	DISF190Y	moderate	Biomarker	[12]
Prostate carcinoma	DISMJPLE	moderate	Biomarker	[12]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[13]
Arrhythmia	DISFF2NI	Limited	Genetic Variation	[14]
Lung cancer	DISCM4YA	Limited	Biomarker	[4]
Lung carcinoma	DISTR26C	Limited	Biomarker	[4]
Pulmonary disease	DIS6060I	Limited	Posttranslational Modification	[13]
Schizophrenia	DISSRV2N	No Known	Unknown	[15]

8 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 Short stature homeobox protein 2 (SHOX2).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Short stature homeobox protein 2 (SHOX2).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Short stature homeobox protein 2 (SHOX2).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Short stature homeobox protein 2 (SHOX2).	[19]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Short stature homeobox protein 2 (SHOX2).	[20]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Short stature homeobox protein 2 (SHOX2).	[21]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Short stature homeobox protein 2 (SHOX2).	[22]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Short stature homeobox protein 2 (SHOX2).	[23]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Short stature homeobox protein 2 (SHOX2).	[24]

References

• [1] A SHOX2 loss-of-function mutation underlying familial atrial fibrillation.Int J Med Sci. 2018 Oct 20;15(13):1564-1572. doi: 10.7150/ijms.27424. eCollection 2018.
• [2] Sex hormone-dependent tRNA halves enhance cell proliferation in breast and prostate cancers.Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):E3816-25. doi: 10.1073/pnas.1510077112. Epub 2015 Jun 29.
• [3] MiR-375 suppresses invasion and metastasis by direct targeting of SHOX2 in esophageal squamous cell carcinoma.Acta Biochim Biophys Sin (Shanghai). 2017 Feb 6;49(2):159-169. doi: 10.1093/abbs/gmw131.
• [4] Short stature homeobox 2 methylation as a potential noninvasive biomarker in bronchial aspirates for lung cancer diagnosis.Oncotarget. 2017 May 22;8(37):61253-61263. doi: 10.18632/oncotarget.18056. eCollection 2017 Sep 22.
• [5] SHOX2 is a Potent Independent Biomarker to Predict Survival of WHO Grade II-III Diffuse Gliomas.EBioMedicine. 2016 Nov;13:80-89. doi: 10.1016/j.ebiom.2016.10.040. Epub 2016 Oct 28.
• [6] Elevated SHOX2 expression is associated with tumor recurrence of hepatocellular carcinoma.Ann Surg Oncol. 2013 Dec;20 Suppl 3:S644-9. doi: 10.1245/s10434-013-3132-1. Epub 2013 Jul 13.
• [7] Replacing Shox2 with human SHOX leads to congenital disc degeneration of the temporomandibular joint in mice.Cell Tissue Res. 2014 Feb;355(2):345-54. doi: 10.1007/s00441-013-1743-2. Epub 2013 Nov 19.
• [8] NPPB and ACAN, two novel SHOX2 transcription targets implicated in skeletal development.PLoS One. 2014 Jan 8;9(1):e83104. doi: 10.1371/journal.pone.0083104. eCollection 2014.
• [9] DNA methylation of the homeobox genes PITX2 and SHOX2 predicts outcome in non-small-cell lung cancer patients.Diagn Mol Pathol. 2012 Jun;21(2):93-104. doi: 10.1097/PDM.0b013e318240503b.
• [10] Cell-Free SHOX2 DNA Methylation in Blood as a Molecular Staging Parameter for Risk Stratification in Renal Cell Carcinoma Patients: A Prospective Observational Cohort Study.Clin Chem. 2019 Apr;65(4):559-568. doi: 10.1373/clinchem.2018.297549. Epub 2019 Jan 9.
• [11] SHOT, a SHOX-related homeobox gene, is implicated in craniofacial, brain, heart, and limb development.Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2406-11. doi: 10.1073/pnas.95.5.2406.
• [12] Single fraction urethra-sparing prostate cancer SBRT: Phase I results of the ONE SHOT trial.Radiother Oncol. 2019 Oct;139:83-86. doi: 10.1016/j.radonc.2019.07.018. Epub 2019 Aug 17.
• [13] The value of SHOX2 methylation test in peripheral blood samples used for the differential diagnosis of lung cancer and other lung disorders.Neoplasma. 2016;63(2):246-53. doi: 10.4149/210_150419N208.
• [14] Functional redundancy between human SHOX and mouse Shox2 genes in the regulation of sinoatrial node formation and pacemaking function.J Biol Chem. 2011 May 13;286(19):17029-38. doi: 10.1074/jbc.M111.234252. Epub 2011 Mar 28.
• [15] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [16] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [17] 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.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [20] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [21] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [22] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [23] Regulation of gene expression and inhibition of experimental prostate cancer bone metastasis by dietary genistein. Neoplasia. 2004 Jul-Aug;6(4):354-63. doi: 10.1593/neo.03478.
• [24] 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.