Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT24PHPM)

• DOT Name: Keratin, type II cytoskeletal 4 (KRT4)
• Synonyms: Cytokeratin-4; CK-4; Keratin-4; K4; Type-II keratin Kb4
• Gene Name: KRT4
• Related Disease:
  Esophageal squamous cell carcinoma
  Squamous cell carcinoma
  Adenocarcinoma
  Anal intraepithelial neoplasia
  Hepatocellular carcinoma
  Neoplasm
  White sponge nevus 1
  Hereditary mucosal leukokeratosis
  Contact dermatitis
  Early-onset parkinsonism-intellectual disability syndrome
  Leukoplakia
• UniProt ID: K2C4_HUMAN
• Pfam ID: PF00038 ; PF16208
• Sequence:
  MIARQQCVRGGPRGFSCGSAIVGGGKRGAFSSVSMSGGAGRCSSGGFGSRSLYNLRGNKS
  ISMSVAGSRQGACFGGAGGFGTGGFGGGFGGSFSGKGGPGFPVCPAGGIQEVTINQSLLT
  PLHVEIDPEIQKVRTEEREQIKLLNNKFASFIDKVQFLEQQNKVLETKWNLLQQQTTTTS
  SKNLEPLFETYLSVLRKQLDTLGNDKGRLQSELKTMQDSVEDFKTKYEEEINKRTAAEND
  FVVLKKDVDAAYLNKVELEAKVDSLNDEINFLKVLYDAELSQMQTHVSDTSVVLSMDNNR
  NLDLDSIIAEVRAQYEEIAQRSKAEAEALYQTKVQQLQISVDQHGDNLKNTKSEIAELNR
  MIQRLRAEIENIKKQCQTLQVSVADAEQRGENALKDAHSKRVELEAALQQAKEELARMLR
  EYQELMSVKLALDIEIATYRKLLEGEEYRMSGECQSAVSISVVSGSTSTGGISGGLGSGS
  GFGLSSGFGSGSGSGFGFGGSVSGSSSSKIISTTTLNKRR
• Tissue Specificity: Detected in the suprabasal layer of the stratified epithelium of the esophagus, exocervix, vagina, mouth and lingual mucosa, and in cells and cell clusters in the mucosa and serous gland ducts of the esophageal submucosa (at protein level). Expressed widely in the exocervix and esophageal epithelium, with lowest levels detected in the basal cell layer.
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Esophageal squamous cell carcinoma	DIS5N2GV	Definitive	Biomarker	[1]
Squamous cell carcinoma	DISQVIFL	Definitive	Altered Expression	[2]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[3]
Anal intraepithelial neoplasia	DISJ0JW3	Strong	Altered Expression	[2]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[4]
White sponge nevus 1	DISF46OE	Strong	Autosomal dominant	[5]
Hereditary mucosal leukokeratosis	DISWAC34	Supportive	Autosomal dominant	[5]
Contact dermatitis	DISQ3AU0	Limited	Biomarker	[6]
Early-onset parkinsonism-intellectual disability syndrome	DIS206QS	Limited	Genetic Variation	[7]
Leukoplakia	DIST3QD3	Limited	Altered Expression	[8]

2 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 Keratin, type II cytoskeletal 4 (KRT4).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Keratin, type II cytoskeletal 4 (KRT4).	[15]

6 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 Keratin, type II cytoskeletal 4 (KRT4).	[10]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Keratin, type II cytoskeletal 4 (KRT4).	[11]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Keratin, type II cytoskeletal 4 (KRT4).	[12]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Keratin, type II cytoskeletal 4 (KRT4).	[13]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Keratin, type II cytoskeletal 4 (KRT4).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Keratin, type II cytoskeletal 4 (KRT4).	[17]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
DNCB	DMDTVYC	Phase 2	DNCB affects the binding of Keratin, type II cytoskeletal 4 (KRT4).	[14]

References

• [1] Fascin and CK4 as biomarkers for esophageal squamous cell carcinoma.Anticancer Res. 2011 Mar;31(3):945-52.
• [2] Down-regulation of keratin 4 and keratin 13 expression in oral squamous cell carcinoma and epithelial dysplasia: a clue for histopathogenesis.Histopathology. 2011 Mar;58(4):531-42. doi: 10.1111/j.1365-2559.2011.03759.x. Epub 2011 Mar 3.
• [3] Transcriptional gene expression profiles of oesophageal adenocarcinoma and normal oesophageal tissues.Anticancer Res. 2003 Jan-Feb;23(1A):161-5.
• [4] Reversion of tumor hepatocytes to normal hepatocytes during liver tumor regression in an oncogene-expressing transgenic zebrafish model.Dis Model Mech. 2019 Oct 17;12(10):dmm039578. doi: 10.1242/dmm.039578.
• [5] A glutamine insertion in the 1A alpha helical domain of the keratin 4 gene in a familial case of white sponge nevus. J Invest Dermatol. 2000 Feb;114(2):388-91. doi: 10.1046/j.1523-1747.2000.00890.x.
• [6] Genes specifically modulated in sensitized skins allow the detection of sensitizers in a reconstructed human skin modelDevelopment of the SENS-IS assay. Toxicol In Vitro. 2015 Jun;29(4):787-802.
• [7] Clinical features and molecular genetic analysis in a Turkish family with oral white sponge nevus.Med Oral Patol Oral Cir Bucal. 2018 Mar 1;23(2):e144-e150. doi: 10.4317/medoral.21437.
• [8] Differential expression of the keratin-4, -13, -14, -17 and transglutaminase 3 genes during the development of oral squamous cell carcinoma from leukoplakia.Oral Oncol. 2005 Jul;41(6):607-13. doi: 10.1016/j.oraloncology.2005.01.011. Epub 2005 Apr 14.
• [9] 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.
• [10] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [11] 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.
• [12] Altered ErbB receptor signaling and gene expression in cisplatin-resistant ovarian cancer. Cancer Res. 2005 Aug 1;65(15):6789-800. doi: 10.1158/0008-5472.CAN-04-2684.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] Proteomic analysis of the cellular response to a potent sensitiser unveils the dynamics of haptenation in living cells. Toxicology. 2020 Dec 1;445:152603. doi: 10.1016/j.tox.2020.152603. Epub 2020 Sep 28.
• [15] 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.
• [16] Low dose of bisphenol a modulates ovarian cancer gene expression profile and promotes epithelial to mesenchymal transition via canonical Wnt pathway. Toxicol Sci. 2018 Aug 1;164(2):527-538.
• [17] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.