Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBSR6C9)

• DOT Name: Homeodomain-only protein (HOPX)
• Synonyms: Lung cancer-associated Y protein; Not expressed in choriocarcinoma protein 1; Odd homeobox protein 1
• Gene Name: HOPX
• Related Disease:
  Adult glioblastoma
  Advanced cancer
  Atrial fibrillation
  Breast cancer
  Breast carcinoma
  Cardiac failure
  Cardiovascular disease
  Choriocarcinoma
  Complete hydatidiform mole
  Congestive heart failure
  Differentiated thyroid carcinoma
  Dilated cardiomyopathy
  Dilated cardiomyopathy 1A
  Esophageal squamous cell carcinoma
  Gastric cancer
  Glioblastoma multiforme
  Head and neck cancer
  Head and neck carcinoma
  High blood pressure
  Hypopharyngeal carcinoma
  Lichen planus
  Lung adenocarcinoma
  Lung cancer
  Lung carcinoma
  Neoplasm
  Obesity
  Pancreatic cancer
  Prostate cancer
  Prostate carcinoma
  Skin disease
  Squamous cell carcinoma
  Stomach cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Type-1/2 diabetes
  Head-neck squamous cell carcinoma
  Influenza
  Lung neoplasm
  Lung squamous cell carcinoma
  Colorectal carcinoma
  Arrhythmia
  Nasopharyngeal carcinoma
  Non-small-cell lung cancer
  Sickle-cell anaemia
• UniProt ID: HOP_HUMAN
• Pfam ID: PF00046
• Sequence:
  MSAETASGPTEDQVEILEYNFNKVDKHPDSTTLCLIAAEAGLSEEETQKWFKQRLAKWRR
  SEGLPSECRSVTD
• Function: Atypical homeodomain protein which does not bind DNA and is required to modulate cardiac growth and development. Acts via its interaction with SRF, thereby modulating the expression of SRF-dependent cardiac-specific genes and cardiac development. Prevents SRF-dependent transcription either by inhibiting SRF binding to DNA or by recruiting histone deacetylase (HDAC) proteins that prevent transcription by SRF. Overexpression causes cardiac hypertrophy. May act as a tumor suppressor. Acts as a co-chaperone for HSPA1A and HSPA1B chaperone proteins and assists in chaperone-mediated protein refolding.
• Tissue Specificity: Widely expressed. Expressed in the heart, brain, placenta, lung, skeletal and smooth muscles, uterus, urinary bladder, kidney and spleen. Down-regulated in some types of cancer such as lung cancer, choriocarcinoma, head and neck squamous cell carcinoma and oral squamous cell carcinoma.

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Strong	Biomarker	[1]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[2]
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Cardiac failure	DISDC067	Strong	Altered Expression	[5]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[6]
Choriocarcinoma	DISDBVNL	Strong	Altered Expression	[7]
Complete hydatidiform mole	DIS5QPI0	Strong	Altered Expression	[8]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[5]
Differentiated thyroid carcinoma	DIS1V20Y	Strong	Posttranslational Modification	[9]
Dilated cardiomyopathy	DISX608J	Strong	Altered Expression	[10]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[10]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Altered Expression	[11]
Gastric cancer	DISXGOUK	Strong	Altered Expression	[2]
Glioblastoma multiforme	DISK8246	Strong	Biomarker	[1]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[12]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[12]
High blood pressure	DISY2OHH	Strong	Biomarker	[13]
Hypopharyngeal carcinoma	DISLOSB4	Strong	Altered Expression	[14]
Lichen planus	DISRPMMS	Strong	Altered Expression	[15]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[16]
Lung cancer	DISCM4YA	Strong	Biomarker	[16]
Lung carcinoma	DISTR26C	Strong	Biomarker	[16]
Neoplasm	DISZKGEW	Strong	Biomarker	[17]
Obesity	DIS47Y1K	Strong	Biomarker	[13]
Pancreatic cancer	DISJC981	Strong	Posttranslational Modification	[18]
Prostate cancer	DISF190Y	Strong	Altered Expression	[19]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[19]
Skin disease	DISDW8R6	Strong	Altered Expression	[15]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[15]
Stomach cancer	DISKIJSX	Strong	Altered Expression	[2]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[20]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Altered Expression	[17]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[13]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Biomarker	[12]
Influenza	DIS3PNU3	moderate	Altered Expression	[21]
Lung neoplasm	DISVARNB	moderate	Altered Expression	[16]
Lung squamous cell carcinoma	DISXPIBD	moderate	Biomarker	[16]
Colorectal carcinoma	DIS5PYL0	Disputed	Posttranslational Modification	[22]
Arrhythmia	DISFF2NI	Limited	Altered Expression	[23]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Posttranslational Modification	[24]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[25]
Sickle-cell anaemia	DIS5YNZB	Limited	Biomarker	[26]

1 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 Homeodomain-only protein (HOPX).	[27]

11 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 Homeodomain-only protein (HOPX).	[28]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Homeodomain-only protein (HOPX).	[29]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Homeodomain-only protein (HOPX).	[30]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Homeodomain-only protein (HOPX).	[31]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Homeodomain-only protein (HOPX).	[32]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Homeodomain-only protein (HOPX).	[33]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Homeodomain-only protein (HOPX).	[34]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Homeodomain-only protein (HOPX).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Homeodomain-only protein (HOPX).	[35]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Homeodomain-only protein (HOPX).	[36]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Homeodomain-only protein (HOPX).	[37]

References

• [1] Regulation of survival in adult hippocampal and glioblastoma stem cell lineages by the homeodomain-only protein HOP.Neural Dev. 2008 May 28;3:13. doi: 10.1186/1749-8104-3-13.
• [2] HSP70/HSP90-Organizing Protein Contributes to Gastric Cancer Progression in an Autocrine Fashion and Predicts Poor Survival in Gastric Cancer.Cell Physiol Biochem. 2018;47(2):879-892. doi: 10.1159/000490080. Epub 2018 May 22.
• [3] Amino Acid-Based Metabolic Panel Provides Robust Prognostic Value Additive to B-Natriuretic Peptide and Traditional Risk Factors in Heart Failure.Dis Markers. 2018 Oct 10;2018:3784589. doi: 10.1155/2018/3784589. eCollection 2018.
• [4] Development of Thiazole-5-carboxylate Derivatives as Selective Inhibitors of Monoacylglycerol Lipase as Target in Cancer.Mini Rev Med Chem. 2019;19(5):410-423. doi: 10.2174/1389557518666180702103542.
• [5] Homeodomain only protein x is down-regulated in human heart failure.J Mol Cell Cardiol. 2011 Jun;50(6):1056-8. doi: 10.1016/j.yjmcc.2011.02.015. Epub 2011 Mar 5.
• [6] Day-by-Day Variability of Home Blood Pressure and Incident Cardiovascular Disease in Clinical Practice: The J-HOP Study (Japan Morning Surge-Home Blood Pressure).Hypertension. 2018 Jan;71(1):177-184. doi: 10.1161/HYPERTENSIONAHA.117.10385. Epub 2017 Nov 13.
• [7] NECC1, a candidate choriocarcinoma suppressor gene that encodes a homeodomain consensus motif.Genomics. 2003 Jan;81(1):15-25. doi: 10.1016/s0888-7543(02)00011-3.
• [8] Genetics and molecular markers in gestational trophoblastic disease with special reference to their clinical application.Best Pract Res Clin Obstet Gynaecol. 2003 Dec;17(6):827-36. doi: 10.1016/s1521-6934(03)00096-8.
• [9] HOPX homeobox methylation in differentiated thyroid cancer and its clinical relevance.Endocr Connect. 2018 Dec;7(12):1333-1342. doi: 10.1530/EC-18-0380.
• [10] Myocardin mRNA is augmented in the failing myocardium: expression profiling in the porcine model and human dilated cardiomyopathy.J Mol Med (Berl). 2003 Sep;81(9):566-77. doi: 10.1007/s00109-003-0470-7. Epub 2003 Aug 13.
• [11] HOP/OB1/NECC1 promoter DNA is frequently hypermethylated and involved in tumorigenic ability in esophageal squamous cell carcinoma.Mol Cancer Res. 2008 Jan;6(1):31-41. doi: 10.1158/1541-7786.MCR-07-0213.
• [12] HOPX functions as a tumour suppressor in head and neck cancer.Sci Rep. 2016 Dec 9;6:38758. doi: 10.1038/srep38758.
• [13] T-HOD: a literature-based candidate gene database for hypertension, obesity and diabetes.Database (Oxford). 2013 Feb 12;2013:bas061. doi: 10.1093/database/bas061. Print 2013.
• [14] Loss of HOP tumour suppressor expression in head and neck squamous cell carcinoma.Br J Cancer. 2004 Jul 19;91(2):258-61. doi: 10.1038/sj.bjc.6601952.
• [15] Homeodomain-only protein HOP is a novel modulator of late differentiation in keratinocytes.Eur J Cell Biol. 2011 Apr;90(4):279-90. doi: 10.1016/j.ejcb.2010.11.001. Epub 2011 Jan 22.
• [16] HOPX is methylated and exerts tumour-suppressive function through Ras-induced senescence in human lung cancer.J Pathol. 2015 Feb;235(3):397-407. doi: 10.1002/path.4469. Epub 2014 Dec 18.
• [17] Epigenetic silencing of HOPX is critically involved in aggressive phenotypes and patient prognosis in papillary thyroid cancer.Oncotarget. 2019 Oct 15;10(57):5906-5918. doi: 10.18632/oncotarget.27187. eCollection 2019 Oct 15.
• [18] Cancer specific promoter CpG Islands hypermethylation of HOP homeobox (HOPX) gene and its potential tumor suppressive role in pancreatic carcinogenesis.BMC Cancer. 2012 Sep 7;12:397. doi: 10.1186/1471-2407-12-397.
• [19] The heat shock protein 70 inhibitor VER155008 suppresses the expression of HSP27, HOP and HSP90 and the androgen receptor, induces apoptosis, and attenuates prostate cancer cell growth.J Cell Biochem. 2020 Jan;121(1):407-417. doi: 10.1002/jcb.29195. Epub 2019 Jun 21.
• [20] A novel homeobox gene overexpressed in thyroid carcinoma.Thyroid. 2004 Jul;14(7):500-5. doi: 10.1089/1050725041517020.
• [21] Type 1 IFN signaling critically regulates influenza-induced alloimmunization to transfused KEL RBCs in a murine model.Transfusion. 2019 Oct;59(10):3243-3252. doi: 10.1111/trf.15482. Epub 2019 Aug 12.
• [22] Methylation of the homeobox gene, HOPX, is frequently detected in poorly differentiated colorectal cancer.Anticancer Res. 2011 Sep;31(9):2889-92.
• [23] Fetal Arrhythmias: Genetic Background and Clinical Implications.Pediatr Cardiol. 2019 Feb;40(2):247-256. doi: 10.1007/s00246-018-2008-3. Epub 2018 Nov 26.
• [24] HOPX hypermethylation promotes metastasis via activating SNAIL transcription in nasopharyngeal carcinoma.Nat Commun. 2017 Feb 1;8:14053. doi: 10.1038/ncomms14053.
• [25] icroRNA?21 promotes the progression of nonsmall cell lung cancer by targeting HOPX and regulating the Wnt/catenin signaling pathway.Mol Med Rep. 2019 Jul;20(1):151-161. doi: 10.3892/mmr.2019.10226. Epub 2019 May 9.
• [26] Alloimmunization to transfused HOD red blood cells is not increased in mice with sickle cell disease.Transfusion. 2012 Feb;52(2):231-40. doi: 10.1111/j.1537-2995.2011.03255.x. Epub 2011 Jul 25.
• [27] 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.
• [28] 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.
• [29] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [30] RNA sequence analysis of inducible pluripotent stem cell-derived cardiomyocytes reveals altered expression of DNA damage and cell cycle genes in response to doxorubicin. Toxicol Appl Pharmacol. 2018 Oct 1;356:44-53.
• [31] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [32] 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.
• [33] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [34] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [35] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [36] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [37] 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.