Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ4MNEW)

• DOT Name: Grainyhead-like protein 1 homolog (GRHL1)
• Synonyms: Mammalian grainyhead; NH32; Transcription factor CP2-like 2; Transcription factor LBP-32
• Gene Name: GRHL1
• Related Disease:
  Advanced cancer
  Atrial fibrillation
  Breast carcinoma
  Cardiac failure
  Clear cell renal carcinoma
  Colon cancer
  Colon carcinoma
  Esophageal squamous cell carcinoma
  Essential hypertension
  High blood pressure
  Neoplasm
  Prostate cancer
  Prostate carcinoma
  Stroke
  Type-1/2 diabetes
  Colorectal carcinoma
  Nasopharyngeal carcinoma
  Neuroblastoma
• UniProt ID: GRHL1_HUMAN
• PDB ID: 5MPF; 5MPH; 5MPI
• Pfam ID: PF04516
• Sequence:
  MTQEYDNKRPVLVLQNEALYPQRRSYTSEDEAWKSFLENPLTAATKAMMSINGDEDSAAA
  LGLLYDYYKVPRERRSSTAKPEVEHPEPDHSKRNSIPIVTEQPLISAGENRVQVLKNVPF
  NIVLPHGNQLGIDKRGHLTAPDTTVTVSIATMPTHSIKTETQPHGFAVGIPPAVYHPEPT
  ERVVVFDRNLNTDQFSSGAQAPNAQRRTPDSTFSETFKEGVQEVFFPSDLSLRMPGMNSE
  DYVFDSVSGNNFEYTLEASKSLRQKPGDSTMTYLNKGQFYPITLKEVSSSEGIHHPISKV
  RSVIMVVFAEDKSREDQLRHWKYWHSRQHTAKQRCIDIADYKESFNTISNIEEIAYNAIS
  FTWDINDEAKVFISVNCLSTDFSSQKGVKGLPLNIQVDTYSYNNRSNKPVHRAYCQIKVF
  CDKGAERKIRDEERKQSKRKVSDVKVPLLPSHKRMDITVFKPFIDLDTQPVLFIPDVHFA
  NLQRGTHVLPIASEELEGEGSVLKRGPYGTEDDFAVPPSTKLARIEEPKRVLLYVRKESE
  EVFDALMLKTPSLKGLMEAISDKYDVPHDKIGKIFKKCKKGILVNMDDNIVKHYSNEDTF
  QLQIEEAGGSYKLTLTEI
• Function: Transcription factor involved in epithelial development. Binds directly to the consensus DNA sequence 5'-AACCGGTT-3'. Important regulator of DSG1 in the context of hair anchorage and epidermal differentiation, participates in the maintenance of the skin barrier. There is no genetic interaction with GRHL3, nor functional cooperativity due to diverse target gene selectivity during epithelia development. May play a role in regulating glucose homeostasis and insulin signaling; [Isoform 1]: Functions as a transcription activator; [Isoform 2]: May function as a repressor in tissues where both isoform 1 and isoform 2 are expressed.
• Tissue Specificity: Isoform 1 is highly expressed in brain, pancreas, tonsil, placenta and kidney. Isoform 2 is highly expressed in brain and liver. Expressed at very low levels in non-steroidogenic cells.
• Reactome Pathway: PPARA activates gene expression (R-HSA-1989781)

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Atrial fibrillation	DIS15W6U	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[3]
Cardiac failure	DISDC067	Strong	Genetic Variation	[2]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[6]
Essential hypertension	DIS7WI98	Strong	Genetic Variation	[7]
High blood pressure	DISY2OHH	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[8]
Prostate cancer	DISF190Y	Strong	Genetic Variation	[9]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[10]
Stroke	DISX6UHX	Strong	Genetic Variation	[2]
Type-1/2 diabetes	DISIUHAP	Strong	Genetic Variation	[2]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[11]
Nasopharyngeal carcinoma	DISAOTQ0	Limited	Genetic Variation	[12]
Neuroblastoma	DISVZBI4	Limited	Altered Expression	[13]

3 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 Grainyhead-like protein 1 homolog (GRHL1).	[14]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Grainyhead-like protein 1 homolog (GRHL1).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Grainyhead-like protein 1 homolog (GRHL1).	[25]

12 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 Grainyhead-like protein 1 homolog (GRHL1).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Grainyhead-like protein 1 homolog (GRHL1).	[16]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Grainyhead-like protein 1 homolog (GRHL1).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Grainyhead-like protein 1 homolog (GRHL1).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Grainyhead-like protein 1 homolog (GRHL1).	[19]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Grainyhead-like protein 1 homolog (GRHL1).	[20]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Grainyhead-like protein 1 homolog (GRHL1).	[21]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Grainyhead-like protein 1 homolog (GRHL1).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Grainyhead-like protein 1 homolog (GRHL1).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Grainyhead-like protein 1 homolog (GRHL1).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Grainyhead-like protein 1 homolog (GRHL1).	[27]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Grainyhead-like protein 1 homolog (GRHL1).	[28]

References

• [1] Roles of Grainyhead-like transcription factors in cancer.Oncogene. 2017 Nov 2;36(44):6067-6073. doi: 10.1038/onc.2017.178. Epub 2017 Jul 17.
• [2] Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.Front Genet. 2016 Oct 13;7:179. doi: 10.3389/fgene.2016.00179. eCollection 2016.
• [3] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [4] Potential protective role of Grainyhead-like genes in the development of clear cell renal cell carcinoma.Mol Carcinog. 2017 Nov;56(11):2414-2423. doi: 10.1002/mc.22682. Epub 2017 Jun 15.
• [5] Anti-sense RNA of 32-kDa laminin-binding protein inhibits attachment and invasion of a human colon carcinoma cell line.J Surg Res. 1992 Apr;52(4):340-6. doi: 10.1016/0022-4804(92)90113-e.
• [6] Suppressor gene GRHL1 is associated with prognosis in patients with oesophageal squamous cell carcinoma.Oncol Lett. 2019 May;17(5):4313-4320. doi: 10.3892/ol.2019.10072. Epub 2019 Feb 25.
• [7] Effects of high and low sodium diet on blood pressure and heart rate in mice lacking the functional grainyhead-like 1 gene.Physiol Res. 2017 Mar 31;66(1):163-165. doi: 10.33549/physiolres.933298. Epub 2016 Oct 26.
• [8] Coordinated expression and genetic polymorphisms in Grainyhead-like genes in human non-melanoma skin cancers.BMC Cancer. 2018 Jan 4;18(1):23. doi: 10.1186/s12885-017-3943-8.
• [9] Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array.Nat Genet. 2013 Apr;45(4):385-91, 391e1-2. doi: 10.1038/ng.2560.
• [10] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [11] Expression of 32-kDa laminin-binding protein mRNA in colon cancer tissues.J Surg Res. 1996 Feb 15;61(1):120-6. doi: 10.1006/jsre.1996.0091.
• [12] Retrospective dosimetry study of intensity-modulated radiation therapy for nasopharyngeal carcinoma: measurement-guided dose reconstruction and analysis.Radiat Oncol. 2018 Mar 15;13(1):42. doi: 10.1186/s13014-018-0993-2.
• [13] GRHL1 acts as tumor suppressor in neuroblastoma and is negatively regulated by MYCN and HDAC3.Cancer Res. 2014 May 1;74(9):2604-16. doi: 10.1158/0008-5472.CAN-13-1904. Epub 2014 Jan 13.
• [14] Integrated 'omics analysis reveals new drug-induced mitochondrial perturbations in human hepatocytes. Toxicol Lett. 2018 Jun 1;289:1-13.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [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] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [18] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [19] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [20] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [21] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [22] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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.
• [25] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [26] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [27] 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.
• [28] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.