Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4JGKJF)

• DOT Name: Homer protein homolog 2 (HOMER2)
• Synonyms: Homer-2; Cupidin
• Gene Name: HOMER2
• Related Disease:
  Alzheimer disease
  Autosomal dominant nonsyndromic hearing loss 68
  Cocaine addiction
  Endometrial cancer
  Endometrial carcinoma
  Familial multiple trichoepithelioma
  Schizophrenia
  Sensorineural hearing loss disorder
  Substance abuse
  Acute myelogenous leukaemia
  Nonsyndromic genetic hearing loss
  Stroke
  Autosomal dominant nonsyndromic hearing loss
  Anxiety
  Anxiety disorder
  Cognitive impairment
  Colorectal carcinoma
  Rectal adenocarcinoma
  Rectal carcinoma
• UniProt ID: HOME2_HUMAN
• Pfam ID: PF00568
• Sequence:
  MGEQPIFTTRAHVFQIDPNTKKNWMPASKQAVTVSYFYDVTRNSYRIISVDGAKVIINST
  ITPNMTFTKTSQKFGQWADSRANTVFGLGFSSEQQLTKFAEKFQEVKEAAKIAKDKTQEK
  IETSSNHSQESGRETPSSTQASSVNGTDDEKASHAGPANTHLKSENDKLKIALTQSAANV
  KKWEIELQTLRESNARLTTALQESAASVEQWKRQFSICRDENDRLRNKIDELEEQCSEIN
  REKEKNTQLKRRIEELEAELREKETELKDLRKQSEIIPQLMSECEYVSEKLEAAERDNQN
  LEDKVRSLKTDIEESKYRQRHLKVELKSFLEVLDGKIDDLHDFRRGLSKLGTDN
• Function: Postsynaptic density scaffolding protein. Binds and cross-links cytoplasmic regions of GRM1, GRM5, ITPR1, DNM3, RYR1, RYR2, SHANK1 and SHANK3. By physically linking GRM1 and GRM5 with ER-associated ITPR1 receptors, it aids the coupling of surface receptors to intracellular calcium release. May also couple GRM1 to PI3 kinase through its interaction with AGAP2. Isoforms can be differently regulated and may play an important role in maintaining the plasticity at glutamatergic synapses. Required for normal hearing. Negatively regulates T cell activation by inhibiting the calcineurin-NFAT pathway. Acts by competing with calcineurin/PPP3CA for NFAT protein binding, hence preventing NFAT activation by PPP3CA.
• KEGG Pathway:
  FoxO sig.ling pathway (hsa04068)
  Glutamatergic sy.pse (hsa04724)
• Reactome Pathway: Neurexins and neuroligins (R-HSA-6794361)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[1]
Autosomal dominant nonsyndromic hearing loss 68	DISGUBO8	Strong	Autosomal dominant	[2]
Cocaine addiction	DISHTRXG	Strong	Genetic Variation	[3]
Endometrial cancer	DISW0LMR	Strong	Altered Expression	[4]
Endometrial carcinoma	DISXR5CY	Strong	Altered Expression	[4]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Altered Expression	[4]
Schizophrenia	DISSRV2N	Strong	Biomarker	[5]
Sensorineural hearing loss disorder	DISJV45Z	Strong	Genetic Variation	[6]
Substance abuse	DIS327VW	Strong	Genetic Variation	[3]
Acute myelogenous leukaemia	DISCSPTN	moderate	Genetic Variation	[7]
Nonsyndromic genetic hearing loss	DISZX61P	Moderate	Autosomal dominant	[8]
Stroke	DISX6UHX	moderate	Biomarker	[9]
Autosomal dominant nonsyndromic hearing loss	DISYC1G0	Supportive	Autosomal dominant	[2]
Anxiety	DISIJDBA	Disputed	Biomarker	[10]
Anxiety disorder	DISBI2BT	Disputed	Biomarker	[10]
Cognitive impairment	DISH2ERD	Limited	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	Limited	Biomarker	[12]
Rectal adenocarcinoma	DIS8R9VO	Limited	Altered Expression	[13]
Rectal carcinoma	DIS8FRR7	Limited	Altered Expression	[13]

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 Homer protein homolog 2 (HOMER2).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Homer protein homolog 2 (HOMER2).	[27]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Homer protein homolog 2 (HOMER2).	[15]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Homer protein homolog 2 (HOMER2).	[16]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Homer protein homolog 2 (HOMER2).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Homer protein homolog 2 (HOMER2).	[18]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Homer protein homolog 2 (HOMER2).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Homer protein homolog 2 (HOMER2).	[20]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Homer protein homolog 2 (HOMER2).	[21]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Homer protein homolog 2 (HOMER2).	[22]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Homer protein homolog 2 (HOMER2).	[23]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Homer protein homolog 2 (HOMER2).	[24]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Homer protein homolog 2 (HOMER2).	[25]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Homer protein homolog 2 (HOMER2).	[26]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Homer protein homolog 2 (HOMER2).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Homer protein homolog 2 (HOMER2).	[29]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Homer protein homolog 2 (HOMER2).	[30]

References

• [1] Linking Genetics of Brain Changes to Alzheimer's Disease: Sparse Whole Genome Association Scan of Regional MRI Volumes in the ADNI and AddNeuroMed Cohorts.J Alzheimers Dis. 2015;45(3):851-64. doi: 10.3233/JAD-142214.
• [2] HOMER2, a stereociliary scaffolding protein, is essential for normal hearing in humans and mice. PLoS Genet. 2015 Mar 27;11(3):e1005137. doi: 10.1371/journal.pgen.1005137. eCollection 2015 Mar.
• [3] Association of a polymorphism in the Homer1 gene with cocaine dependence in an African American population. Psychiatr Genet. 2005 Dec;15(4):277-83. doi: 10.1097/00041444-200512000-00010.
• [4] Overexpression of HOMER2 predicts better outcome in low-grade endometrioid endometrial adenocarcinoma.Pathology. 2018 Aug;50(5):499-503. doi: 10.1016/j.pathol.2018.03.004. Epub 2018 Jun 8.
• [5] Replicated genetic evidence supports a role for HOMER2 in schizophrenia.Neurosci Lett. 2010 Jan 14;468(3):229-33. doi: 10.1016/j.neulet.2009.11.003. Epub 2009 Nov 13.
• [6] Whole exome sequencing identified a second pathogenic variant in HOMER2 for autosomal dominant non-syndromic deafness.Clin Genet. 2018 Nov;94(5):419-428. doi: 10.1111/cge.13422.
• [7] Genome-wide haplotype association study identify the FGFR2 gene as a risk gene for acute myeloid leukemia.Oncotarget. 2017 Jan 31;8(5):7891-7899. doi: 10.18632/oncotarget.13631.
• [8] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [9] Diagnostic Potential of Differentially Expressed Homer1 and Homer2 in Ischemic Stroke.Cell Physiol Biochem. 2016;39(6):2353-2363. doi: 10.1159/000447927. Epub 2016 Nov 11.
• [10] Homer2 within the central nucleus of the amygdala modulates withdrawal-induced anxiety in a mouse model of binge-drinking.Neuropharmacology. 2018 Jan;128:448-459. doi: 10.1016/j.neuropharm.2017.11.001. Epub 2017 Nov 3.
• [11] Recurrent microdeletions of 15q25.2 are associated with increased risk of congenital diaphragmatic hernia, cognitive deficits and possibly Diamond--Blackfan anaemia.J Med Genet. 2010 Nov;47(11):777-81. doi: 10.1136/jmg.2009.075903. Epub 2010 Oct 4.
• [12] Novel candidate colorectal cancer biomarkers identified by methylation microarray-based scanning.Endocr Relat Cancer. 2011 Jul 4;18(4):465-78. doi: 10.1530/ERC-11-0083. Print 2011 Aug.
• [13] Identification of two novel biomarkers of rectal carcinoma progression and prognosis via co-expression network analysis.Oncotarget. 2017 Jun 27;8(41):69594-69609. doi: 10.18632/oncotarget.18646. eCollection 2017 Sep 19.
• [14] 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.
• [15] 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.
• [16] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [17] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] 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.
• [20] A comprehensive analysis of Wnt/beta-catenin signaling pathway-related genes and crosstalk pathways in the treatment of As2O3 in renal cancer. Ren Fail. 2018 Nov;40(1):331-339.
• [21] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [22] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [23] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [24] Differential effects of resveratrol on androgen-responsive LNCaP human prostate cancer cells in vitro and in vivo. Carcinogenesis. 2008 Oct;29(10):2001-10.
• [25] Using DNA microarray analyses to elucidate the effects of genistein in androgen-responsive prostate cancer cells: identification of novel targets. Mol Carcinog. 2004 Oct;41(2):108-119.
• [26] 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.
• [27] Gene expression and cytosine DNA methylation alterations in induced pluripotent stem-cell-derived human hepatocytes treated with low doses of chemical carcinogens. Arch Toxicol. 2019 Nov;93(11):3335-3344. doi: 10.1007/s00204-019-02569-5. Epub 2019 Sep 25.
• [28] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [30] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.