Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA10UCH)

• DOT Name: Keratin, type I cytoskeletal 9 (KRT9)
• Synonyms: Cytokeratin-9; CK-9; Keratin-9; K9
• Gene Name: KRT9
• Related Disease:
  Epidermolytic palmoplantar keratoderma
  Bladder cancer
  Epithelial ovarian cancer
  Keratinization disease
  Ovarian cancer
  Ovarian neoplasm
  Palmoplantar keratosis
  Skin disease
  Urinary bladder cancer
  Urinary bladder neoplasm
  Epidermolytic ichthyosis
  Squamous cell carcinoma
  Epidermolysis bullosa simplex
  Hereditary palmoplantar keratoderma
  Pachyonychia congenita
• UniProt ID: K1C9_HUMAN
• Pfam ID: PF00038
• Sequence:
  MSCRQFSSSYLSRSGGGGGGGLGSGGSIRSSYSRFSSSGGGGGGGRFSSSSGYGGGSSRV
  CGRGGGGSFGYSYGGGSGGGFSASSLGGGFGGGSRGFGGASGGGYSSSGGFGGGFGGGSG
  GGFGGGYGSGFGGFGGFGGGAGGGDGGILTANEKSTMQELNSRLASYLDKVQALEEANND
  LENKIQDWYDKKGPAAIQKNYSPYYNTIDDLKDQIVDLTVGNNKTLLDIDNTRMTLDDFR
  IKFEMEQNLRQGVDADINGLRQVLDNLTMEKSDLEMQYETLQEELMALKKNHKEEMSQLT
  GQNSGDVNVEINVAPGKDLTKTLNDMRQEYEQLIAKNRKDIENQYETQITQIEHEVSSSG
  QEVQSSAKEVTQLRHGVQELEIELQSQLSKKAALEKSLEDTKNRYCGQLQMIQEQISNLE
  AQITDVRQEIECQNQEYSLLLSIKMRLEKEIETYHNLLEGGQEDFESSGAGKIGLGGRGG
  SGGSYGRGSRGGSGGSYGGGGSGGGYGGGSGSRGGSGGSYGGGSGSGGGSGGGYGGGSGG
  GHSGGSGGGHSGGSGGNYGGGSGSGGGSGGGYGGGSGSRGGSGGSHGGGSGFGGESGGSY
  GGGEEASGSGGGYGGGSGKSSHS
• Function: May serve an important special function either in the mature palmar and plantar skin tissue or in the morphogenetic program of the formation of these tissues. Plays a role in keratin filament assembly.
• Tissue Specificity: Expressed in the terminally differentiated epidermis of palms and soles.
• KEGG Pathway:
  Estrogen sig.ling pathway (hsa04915)
  Staphylococcus aureus infection (hsa05150)
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epidermolytic palmoplantar keratoderma	DISBZU6Y	Definitive	Autosomal dominant	[1]
Bladder cancer	DISUHNM0	Strong	Biomarker	[2]
Epithelial ovarian cancer	DIS56MH2	Strong	Genetic Variation	[3]
Keratinization disease	DISD4UB1	Strong	Genetic Variation	[4]
Ovarian cancer	DISZJHAP	Strong	Genetic Variation	[3]
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[3]
Palmoplantar keratosis	DISYQGFB	Strong	Genetic Variation	[5]
Skin disease	DISDW8R6	Strong	Altered Expression	[6]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[2]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[2]
Epidermolytic ichthyosis	DISJPEP3	moderate	Genetic Variation	[7]
Squamous cell carcinoma	DISQVIFL	moderate	Altered Expression	[8]
Epidermolysis bullosa simplex	DIS2CZ6X	Limited	Genetic Variation	[9]
Hereditary palmoplantar keratoderma	DISRA08K	Limited	Genetic Variation	[10]
Pachyonychia congenita	DISW8VPN	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Keratin, type I cytoskeletal 9 (KRT9).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Keratin, type I cytoskeletal 9 (KRT9).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Keratin, type I cytoskeletal 9 (KRT9).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Keratin, type I cytoskeletal 9 (KRT9).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Keratin, type I cytoskeletal 9 (KRT9).	[15]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Keratin, type I cytoskeletal 9 (KRT9).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Keratin, type I cytoskeletal 9 (KRT9).	[18]
9-hydroxyoctadecadienoic acid	DM0FWNJ	Investigative	9-hydroxyoctadecadienoic acid decreases the expression of Keratin, type I cytoskeletal 9 (KRT9).	[19]

1 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 increases the methylation of Keratin, type I cytoskeletal 9 (KRT9).	[17]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Drug-induced keratin 9 interaction with Hsp70 in bladder cancer cells.Cell Stress Chaperones. 2018 Sep;23(5):1137-1142. doi: 10.1007/s12192-018-0913-2. Epub 2018 May 25.
• [3] Epidermolytic palmoplantar keratoderma cosegregates with a keratin 9 mutation in a pedigree with breast and ovarian cancer.Nat Genet. 1994 Jan;6(1):106-10. doi: 10.1038/ng0194-106.
• [4] A novel mutation of a leucine residue in coil 1A of keratin 9 in epidermolytic palmoplantar keratoderma.J Invest Dermatol. 1997 Jul;109(1):113-5. doi: 10.1111/1523-1747.ep12276751.
• [5] Identification of the keratin 9 (KRT9) N161S mutation in a Chinese kindred with epidermolytic palmoplantar keratoderma.Eur J Dermatol. 2008 Jul-Aug;18(4):387-90. doi: 10.1684/ejd.2008.0432. Epub 2008 Jun 23.
• [6] To Control Site-Specific Skin Gene Expression, Autocrine Mimics Paracrine Canonical Wnt Signaling and Is Activated Ectopically in Skin Disease.Am J Pathol. 2016 May;186(5):1140-50. doi: 10.1016/j.ajpath.2015.12.030.
• [7] Atypical epidermolytic palmoplantar keratoderma presentation associated with a mutation in the keratin 1 gene.Br J Dermatol. 2004 Jun;150(6):1096-103. doi: 10.1111/j.1365-2133.2004.05967.x.
• [8] Differentiating cutaneous squamous cell carcinoma and pseudoepitheliomatous hyperplasia by multiplex qRT-PCR.Mod Pathol. 2013 Nov;26(11):1433-7. doi: 10.1038/modpathol.2013.82. Epub 2013 May 24.
• [9] JSID Tanioku Memorial Lecture 1996. Genetic disorders of keratins and their associated proteins.J Dermatol Sci. 1996 Dec;13(3):181-92. doi: 10.1016/s0923-1811(96)00568-3.
• [10] Keratin 9 point mutation in the pedigree of epidermolytic hereditary palmoplantar keratoderma perturbs keratin intermediate filament network formation.FEBS Lett. 1996 May 20;386(2-3):149-55. doi: 10.1016/0014-5793(96)00393-6.
• [11] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [12] Expression Profiling of Human Pluripotent Stem Cell-Derived Cardiomyocytes Exposed to Doxorubicin-Integration and Visualization of Multi-Omics Data. Toxicol Sci. 2018 May 1;163(1):182-195. doi: 10.1093/toxsci/kfy012.
• [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] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [16] Identification of potential biomarkers for predicting acute dermal irritation by proteomic analysis. J Appl Toxicol. 2011 Nov;31(8):762-72.
• [17] 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.
• [18] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [19] A proteomic analysis of acute leukemia cells treated with 9-hydroxyoctadecadienoic acid. Lipids Health Dis. 2016 Nov 10;15(1):192. doi: 10.1186/s12944-016-0359-4.