Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1V4ZEH)

• DOT Name: Grainyhead-like protein 3 homolog (GRHL3)
• Synonyms: Sister of mammalian grainyhead; Transcription factor CP2-like 4
• Gene Name: GRHL3
• Related Disease:
  Cleft palate
  Cleft soft palate
  Isolated cleft palate
  Van der Woude syndrome 1
  Alzheimer disease
  Classic Hodgkin lymphoma
  Cleft lip/palate
  Cutaneous squamous cell carcinoma
  Depression
  Major depressive disorder
  Medulloblastoma
  Mental disorder
  Neoplasm
  Neural tube defect
  Oral mucositis
  Orofacial cleft
  Psoriasis
  Schizophrenia
  Van der Woude syndrome 2
  Van der Woude syndrome
  Advanced cancer
  Branchiooculofacial syndrome
  GNE myopathy
  High blood pressure
  Rheumatoid arthritis
  Skin carcinoma
  Timothy syndrome
  Tourette syndrome
  Tuberous sclerosis
• UniProt ID: GRHL3_HUMAN
• Pfam ID: PF04516
• Sequence:
  MSNELDFRSVRLLKNDPVNLQKFSYTSEDEAWKTYLENPLTAATKAMMRVNGDDDSVAAL
  SFLYDYYMGPKEKRILSSSTGGRNDQGKRYYHGMEYETDLTPLESPTHLMKFLTENVSGT
  PEYPDLLKKNNLMSLEGALPTPGKAAPLPAGPSKLEAGSVDSYLLPTTDMYDNGSLNSLF
  ESIHGVPPTQRWQPDSTFKDDPQESMLFPDILKTSPEPPCPEDYPSLKSDFEYTLGSPKA
  IHIKSGESPMAYLNKGQFYPVTLRTPAGGKGLALSSNKVKSVVMVVFDNEKVPVEQLRFW
  KHWHSRQPTAKQRVIDVADCKENFNTVEHIEEVAYNALSFVWNVNEEAKVFIGVNCLSTD
  FSSQKGVKGVPLNLQIDTYDCGLGTERLVHRAVCQIKIFCDKGAERKMRDDERKQFRRKV
  KCPDSSNSGVKGCLLSGFRGNETTYLRPETDLETPPVLFIPNVHFSSLQRSGGAAPSAGP
  SSSNRLPLKRTCSPFTEEFEPLPSKQAKEGDLQRVLLYVRRETEEVFDALMLKTPDLKGL
  RNAISEKYGFPEENIYKVYKKCKRGETSLLHPRLSRHPPPDCLECSHPVTQVRNMGFGDG
  FWRQRDLDSNPSPTTVNSLHFTVNSE
• Function: Transcription factor playing important roles in primary neurulation and in the differentiation of stratified epithelia of both ectodermal and endodermal origin. Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' acting as an activator and repressor on distinct target genes. xhibits functional redundancy with GRHL2 in epidermal morphogenetic events and epidermal wound repair. Exhibits functional redundancy with GRHL2 in epidermal morphogenetic events and epidermal wound repair but is essential to form the epidermal barrier with TGM3 as critical direct target gene among others. Despite being dispensable during normal epidermal homeostasis in the adulthood, is again required for barrier repair after immune-mediated epidermal damage, regulates distinct gene batteries in embryonic epidermal differentiation and adult epidermal barrier reformation after injury. Plays unique and cooperative roles with GRHL2 in establishing distinct zones of primary neurulation. Essential for spinal closure, functions cooperatively with GRHL2 in closure 2 (forebrain/midbrain boundary) and posterior neuropore closure. Also required for proper development of the oral periderm. No genetic interaction with GRHL3, no functional cooperativity due to diverse target gene selectivity.
• Tissue Specificity: Expressed in brain, colon, pancreas, placenta and kidney. Isoform 1 is expressed in lung and tonsil. Isoform 2 is prostate-specific.

Molecular Interaction Atlas (MIA) of This DOT

29 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cleft palate	DIS6G5TF	Definitive	Biomarker	[1]
Cleft soft palate	DISCN11I	Definitive	SusceptibilityMutation	[2]
Isolated cleft palate	DISV80CD	Definitive	Biomarker	[1]
Van der Woude syndrome 1	DIS8EHBM	Definitive	Autosomal dominant	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Classic Hodgkin lymphoma	DISV1LU6	Strong	Biomarker	[5]
Cleft lip/palate	DIS14IG3	Strong	Genetic Variation	[6]
Cutaneous squamous cell carcinoma	DIS3LXUG	Strong	Altered Expression	[7]
Depression	DIS3XJ69	Strong	Altered Expression	[8]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[9]
Medulloblastoma	DISZD2ZL	Strong	Biomarker	[10]
Mental disorder	DIS3J5R8	Strong	Altered Expression	[11]
Neoplasm	DISZKGEW	Strong	Altered Expression	[12]
Neural tube defect	DIS5J95E	Strong	Genetic Variation	[13]
Oral mucositis	DISS93V5	Strong	Biomarker	[14]
Orofacial cleft	DIST1HG6	Strong	Biomarker	[3]
Psoriasis	DIS59VMN	Strong	Altered Expression	[15]
Schizophrenia	DISSRV2N	Strong	Biomarker	[16]
Van der Woude syndrome 2	DIS4G3U8	Strong	Autosomal dominant	[17]
Van der Woude syndrome	DISADZS1	Supportive	Autosomal dominant	[3]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[18]
Branchiooculofacial syndrome	DISHJ9O9	Limited	Genetic Variation	[19]
GNE myopathy	DIS73X4W	Limited	Biomarker	[20]
High blood pressure	DISY2OHH	Limited	Genetic Variation	[21]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[22]
Skin carcinoma	DISUZREN	Limited	Genetic Variation	[7]
Timothy syndrome	DISBXBZP	Limited	Biomarker	[23]
Tourette syndrome	DISX9D54	Limited	Biomarker	[23]
Tuberous sclerosis	DISEMUGZ	Limited	Biomarker	[23]

11 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 Grainyhead-like protein 3 homolog (GRHL3).	[24]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Grainyhead-like protein 3 homolog (GRHL3).	[25]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Grainyhead-like protein 3 homolog (GRHL3).	[26]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Grainyhead-like protein 3 homolog (GRHL3).	[27]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Grainyhead-like protein 3 homolog (GRHL3).	[28]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Grainyhead-like protein 3 homolog (GRHL3).	[29]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Grainyhead-like protein 3 homolog (GRHL3).	[27]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Grainyhead-like protein 3 homolog (GRHL3).	[27]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Grainyhead-like protein 3 homolog (GRHL3).	[31]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Grainyhead-like protein 3 homolog (GRHL3).	[33]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Grainyhead-like protein 3 homolog (GRHL3).	[34]

2 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 decreases the methylation of Grainyhead-like protein 3 homolog (GRHL3).	[30]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Grainyhead-like protein 3 homolog (GRHL3).	[32]

References

• [1] A systematic genetic analysis and visualization of phenotypic heterogeneity among orofacial cleft GWAS signals.Genet Epidemiol. 2019 Sep;43(6):704-716. doi: 10.1002/gepi.22214. Epub 2019 Jun 6.
• [2] A Genome-wide Association Study of Nonsyndromic Cleft Palate Identifies an Etiologic Missense Variant in GRHL3.Am J Hum Genet. 2016 Apr 7;98(4):744-54. doi: 10.1016/j.ajhg.2016.02.014. Epub 2016 Mar 24.
• [3] Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development. Am J Hum Genet. 2014 Jan 2;94(1):23-32. doi: 10.1016/j.ajhg.2013.11.009. Epub 2013 Dec 19.
• [4] Somatostatin and Neuropeptide Y in Cerebrospinal Fluid: Correlations With Amyloid Peptides A(1-42) and Tau Proteins in Elderly Patients With Mild Cognitive Impairment.Front Aging Neurosci. 2018 Oct 1;10:297. doi: 10.3389/fnagi.2018.00297. eCollection 2018.
• [5] Simultaneous intrinsic signal imaging of auditory and visual cortex reveals profound effects of acute hearing loss on visual processing.Neuroimage. 2017 Oct 1;159:459-472. doi: 10.1016/j.neuroimage.2017.07.037. Epub 2017 Jul 20.
• [6] Disrupted IRF6-NME1/2 Complexes as a Cause of Cleft Lip/Palate.J Dent Res. 2017 Oct;96(11):1330-1338. doi: 10.1177/0022034517723615. Epub 2017 Aug 2.
• [7] Threonine 454 phosphorylation in Grainyhead-like 3 is important for its function and regulation by the p38 MAPK pathway.Biochim Biophys Acta Mol Cell Res. 2018 Jul;1865(7):1002-1011. doi: 10.1016/j.bbamcr.2018.04.010. Epub 2018 Apr 25.
• [8] Distribution of depression, somatization and pain-related impairment in patients with chronic temporomandibular disorders.J Appl Oral Sci. 2019 Jan 7;27:e20180210. doi: 10.1590/1678-7757-2018-0210.
• [9] Loss of Glutamate Decarboxylase 67 in Somatostatin-Expressing Neurons Leads to Anxiety-Like Behavior and Alteration in the Akt/GSK3 Signaling Pathway.Front Behav Neurosci. 2019 Jun 18;13:131. doi: 10.3389/fnbeh.2019.00131. eCollection 2019.
• [10] Clustering of self-organizing map identifies five distinct medulloblastoma subgroups.Cancer Biomark. 2016;16(3):327-32. doi: 10.3233/CBM-160570.
• [11] Somatostatin-IRES-Cre Mice: Between Knockout and Wild-Type?.Front Endocrinol (Lausanne). 2017 Jun 19;8:131. doi: 10.3389/fendo.2017.00131. eCollection 2017.
• [12] Stage-dependent therapeutic efficacy in PI3K/mTOR-driven squamous cell carcinoma of the skin.Cell Death Differ. 2018 Jun;25(6):1146-1159. doi: 10.1038/s41418-017-0032-0. Epub 2017 Dec 13.
• [13] Genetic variants in GRHL3 and risk for neural tube defects: A case-control and case-parent triad/control study.Birth Defects Res. 2019 Nov 15;111(19):1468-1478. doi: 10.1002/bdr2.1556. Epub 2019 Jul 22.
• [14] Randomized Phase 2 Trial of a Novel Clonidine Mucoadhesive Buccal Tablet for the Amelioration of Oral Mucositis in Patients Treated With Concomitant Chemoradiation Therapy for Head and Neck Cancer.Int J Radiat Oncol Biol Phys. 2020 Feb 1;106(2):320-328. doi: 10.1016/j.ijrobp.2019.10.023. Epub 2019 Oct 25.
• [15] The Grainyhead transcription factor Grhl3/Get1 suppresses miR-21 expression and tumorigenesis in skin: modulation of the miR-21 target MSH2 by RNA-binding protein DND1.Oncogene. 2013 Mar 21;32(12):1497-507. doi: 10.1038/onc.2012.168. Epub 2012 May 21.
• [16] Somatostatin Interneurons Facilitate Hippocampal-Prefrontal Synchrony and Prefrontal Spatial Encoding.Neuron. 2018 Nov 21;100(4):926-939.e3. doi: 10.1016/j.neuron.2018.09.029. Epub 2018 Oct 11.
• [17] The functions of grainy head-like proteins in animals and fungi and the evolution of apical extracellular barriers. PLoS One. 2012;7(5):e36254. doi: 10.1371/journal.pone.0036254. Epub 2012 May 9.
• [18] 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.
• [19] Toward an orofacial gene regulatory network.Dev Dyn. 2016 Mar;245(3):220-32. doi: 10.1002/dvdy.24341. Epub 2015 Sep 17.
• [20] Brain metastases in non-small cell lung cancer patients on epidermal growth factor receptor tyrosine kinase inhibitors: symptom and economic burden.J Med Econ. 2017 Nov;20(11):1136-1147. doi: 10.1080/13696998.2017.1361960. Epub 2017 Aug 14.
• [21] Neuropeptide changes in the suprachiasmatic nucleus are associated with the development of hypertension.Chronobiol Int. 2019 Aug;36(8):1072-1087. doi: 10.1080/07420528.2019.1613424. Epub 2019 May 29.
• [22] Modulation of synovial cell function by somatostatin in patients with rheumatoid arthritis.Arthritis Rheum. 1997 Dec;40(12):2128-38. doi: 10.1002/art.1780401206.
• [23] Improved crop yield and reduced nitrate nitrogen leaching with straw return in a rice-wheat rotation of Ningxia irrigation district.Sci Rep. 2018 Jun 21;8(1):9458. doi: 10.1038/s41598-018-27776-5.
• [24] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [25] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [26] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [27] 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.
• [28] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [29] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [30] 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.
• [31] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [32] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [33] 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.
• [34] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.