Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAORBR4)

• DOT Name: Cornulin (CRNN)
• Synonyms: 53 kDa putative calcium-binding protein; 53 kDa squamous epithelial-induced stress protein; 58 kDa heat shock protein; Squamous epithelial heat shock protein 53; Tumor-related protein
• Gene Name: CRNN
• Related Disease:
  Advanced cancer
  Asthma
  Atopic dermatitis
  Esophageal cancer
  Esophageal squamous cell carcinoma
  Gastroesophageal reflux disease
  Neoplasm
  Neoplasm of esophagus
  Psoriasis
  Squamous cell carcinoma
  Carcinoma of esophagus
• UniProt ID: CRNN_HUMAN
• Pfam ID: PF01023
• Sequence:
  MPQLLQNINGIIEAFRRYARTEGNCTALTRGELKRLLEQEFADVIVKPHDPATVDEVLRL
  LDEDHTGTVEFKEFLVLVFKVAQACFKTLSESAEGACGSQESGSLHSGASQELGEGQRSG
  TEVGRAGKGQHYEGSSHRQSQQGSRGQNRPGVQTQGQATGSAWVSSYDRQAESQSQERIS
  PQIQLSGQTEQTQKAGEGKRNQTTEMRPERQPQTREQDRAHQTGETVTGSGTQTQAGATQ
  TVEQDSSHQTGRTSKQTQEATNDQNRGTETHGQGRSQTSQAVTGGHAQIQAGTHTQTPTQ
  TVEQDSSHQTGSTSTQTQESTNGQNRGTEIHGQGRSQTSQAVTGGHTQIQAGSHTETVEQ
  DRSQTVSHGGAREQGQTQTQPGSGQRWMQVSNPEAGETVPGGQAQTGASTESGRQEWSST
  HPRRCVTEGQGDRQPTVVGEEWVDDHSRETVILRLDQGNLHTSVSSAQGQDAAQSEEKRG
  ITARELYSYLRSTKP
• Function: Promotes cell proliferation, G1/S cell cycle progression and induces expression of the cell cycle regulator CCND1. Regulates proliferation induced by pro-inflammatory cytokine response via activation of NFKB1 and PI3K/AKT signaling pathways.
• Tissue Specificity: Expressed in the basal skin layer (at protein level) . Squamous epithelia cell-specific. Expressed in the esophagus (periphery of the cells of the granular and the upper spinous layers), foreskin (granular and lower cornified cells), scalp skin (granular layer), inner root sheath of the hair follicle and in primary keratinocytes (at protein level). Expressed in the squamous epithelium of the cervix, esophagus, foreskin and larynx. Expressed in the fetal bladder and scalp skin. Expressed at very low levels in the lung, kidney, uterus, skeletal muscle, heart and fetal brain. Undetectable or barely detectable in esophageal and oral squamous cell carcinoma compared with the matched adjacent normal esophageal mucosa. Undetectable or barely detectable in larynx and esophagus from patients with pH-documented laryngopharyngeal reflux (LPR).

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Asthma	DISW9QNS	Strong	Genetic Variation	[2]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[2]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[3]
Esophageal squamous cell carcinoma	DIS5N2GV	Strong	Biomarker	[4]
Gastroesophageal reflux disease	DISQ8G5S	Strong	Biomarker	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[3]
Psoriasis	DIS59VMN	Strong	Altered Expression	[1]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[6]
Carcinoma of esophagus	DISS6G4D	Limited	Altered Expression	[3]

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 Cornulin (CRNN).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cornulin (CRNN).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cornulin (CRNN).	[8]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Cornulin (CRNN).	[9]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cornulin (CRNN).	[10]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Cornulin (CRNN).	[8]

References

• [1] Cornulin Is Induced in Psoriasis Lesions and Promotes Keratinocyte Proliferation via Phosphoinositide 3-Kinase/Akt Pathways.J Invest Dermatol. 2019 Jan;139(1):71-80. doi: 10.1016/j.jid.2018.06.184. Epub 2018 Sep 25.
• [2] Altered Expression of Genes Encoding Cornulin and Repetin in Atopic Dermatitis.Int Arch Allergy Immunol. 2017;172(1):11-19. doi: 10.1159/000453452. Epub 2017 Feb 21.
• [3] Loss of CRNN expression is associated with advanced tumor stage and poor survival in patients with esophageal squamous cell carcinoma.J Thorac Cardiovasc Surg. 2014 May;147(5):1612-1618.e4. doi: 10.1016/j.jtcvs.2013.09.066. Epub 2013 Nov 19.
• [4] Ranking candidate genes of esophageal squamous cell carcinomas based on differentially expressed genes and the topological properties of the co-expression network.Eur J Med Res. 2014 Oct 29;19(1):52. doi: 10.1186/s40001-014-0052-x.
• [5] An animal model to evaluate the function and regulation of the adaptively evolving stress protein SEP53 in oesophageal bile damage responses.Cell Stress Chaperones. 2008 Sep;13(3):375-85. doi: 10.1007/s12192-008-0037-1. Epub 2008 May 9.
• [6] Downregulation of CRNN gene and genomic instability at 1q21.3 in oral squamous cell carcinoma.Clin Oral Investig. 2015 Dec;19(9):2273-83. doi: 10.1007/s00784-015-1467-7. Epub 2015 Apr 8.
• [7] 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.
• [8] Retinoic acid and hydroquinone induce inverse expression patterns on cornified envelope-associated proteins: implication in skin irritation. J Dermatol Sci. 2014 Nov;76(2):112-9. doi: 10.1016/j.jdermsci.2014.08.003. Epub 2014 Aug 26.
• [9] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [10] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [11] 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.