Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9RXMPK)

• DOT Name: Keratin, type II cytoskeletal 6C (KRT6C)
• Synonyms: Cytokeratin-6C; CK-6C; Cytokeratin-6E; CK-6E; Keratin K6h; Keratin-6C; K6C; Type-II keratin Kb12
• Gene Name: KRT6C
• Related Disease:
  Epithelial ovarian cancer
  Focal palmoplantar keratoderma
  Ovarian cancer
  Ovarian neoplasm
  Palmoplantar keratoderma, nonepidermolytic, focal or diffuse
  Dental caries
  Pachyonychia congenita
• UniProt ID: K2C6C_HUMAN
• Pfam ID: PF00038 ; PF16208
• Sequence:
  MASTSTTIRSHSSSRRGFSANSARLPGVSRSGFSSISVSRSRGSGGLGGACGGAGFGSRS
  LYGLGGSKRISIGGGSCAISGGYGSRAGGSYGFGGAGSGFGFGGGAGIGFGLGGGAGLAG
  GFGGPGFPVCPPGGIQEVTVNQSLLTPLNLQIDPAIQRVRAEEREQIKTLNNKFASFIDK
  VRFLEQQNKVLDTKWTLLQEQGTKTVRQNLEPLFEQYINNLRRQLDSIVGERGRLDSELR
  NMQDLVEDLKNKYEDEINKRTAAENEFVTLKKDVDAAYMNKVELQAKADTLTDEINFLRA
  LYDAELSQMQTHISDTSVVLSMDNNRNLDLDSIIAEVKAQYEEIAQRSRAEAESWYQTKY
  EELQVTAGRHGDDLRNTKQEIAEINRMIQRLRSEIDHVKKQCASLQAAIADAEQRGEMAL
  KDAKNKLEGLEDALQKAKQDLARLLKEYQELMNVKLALDVEIATYRKLLEGEECRLNGEG
  VGQVNVSVVQSTISSGYGGASGVGSGLGLGGGSSYSYGSGLGIGGGFSSSSGRAIGGGLS
  SVGGGSSTIKYTTTSSSSRKSYKH
• Tissue Specificity: Constitutively expressed in distinct types of epithelia such as those in oral mucosa, esophagus, papillae of tongue and hair follicle outer root sheath.
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[1]
Focal palmoplantar keratoderma	DISGLKBI	Strong	Genetic Variation	[2]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[1]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[1]
Palmoplantar keratoderma, nonepidermolytic, focal or diffuse	DISYUQOY	Strong	Autosomal dominant	[3]
Dental caries	DISRBCMD	Limited	Genetic Variation	[4]
Pachyonychia congenita	DISW8VPN	Limited	Genetic Variation	[5]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Keratin, type II cytoskeletal 6C (KRT6C).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Keratin, type II cytoskeletal 6C (KRT6C).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Keratin, type II cytoskeletal 6C (KRT6C).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Keratin, type II cytoskeletal 6C (KRT6C).	[9]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Keratin, type II cytoskeletal 6C (KRT6C).	[10]
PD-153035	DM7KJTI	Discontinued in Phase 1	PD-153035 decreases the expression of Keratin, type II cytoskeletal 6C (KRT6C).	[10]
chloropicrin	DMSGBQA	Investigative	chloropicrin decreases the expression of Keratin, type II cytoskeletal 6C (KRT6C).	[13]

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 6C (KRT6C).	[11]

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 II cytoskeletal 6C (KRT6C).	[12]

References

• [1] Keratin 5 overexpression is associated with serous ovarian cancer recurrence and chemotherapy resistance.Oncotarget. 2017 Mar 14;8(11):17819-17832. doi: 10.18632/oncotarget.14867.
• [2] Two novel de novo mutations of KRT6A and KRT16 genes in two Chinese pachyonychia congenita pedigrees with fissured tongue or diffuse plantar keratoderma.Eur J Dermatol. 2012 Jul-Aug;22(4):476-80. doi: 10.1684/ejd.2012.1773.
• [3] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [4] Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay.PLoS Genet. 2018 Jan 22;14(1):e1007168. doi: 10.1371/journal.pgen.1007168. eCollection 2018 Jan.
• [5] Revisiting pachyonychia congenita: a case-cohort study of 815 patients.Br J Dermatol. 2020 Mar;182(3):738-746. doi: 10.1111/bjd.18794. Epub 2020 Jan 14.
• [6] Extremely low copper concentrations affect gene expression profiles of human prostate epithelial cell lines. Chem Biol Interact. 2010 Oct 6;188(1):214-9.
• [7] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [8] 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.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] Activation of PPAR and inhibition of cell proliferation reduces key proteins associated with the basal subtype of bladder cancer in As3+-transformed UROtsa cells. PLoS One. 2020 Aug 21;15(8):e0237976. doi: 10.1371/journal.pone.0237976. eCollection 2020.
• [11] 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.
• [12] 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.
• [13] Molecular targets of chloropicrin in human airway epithelial cells. Toxicol In Vitro. 2017 Aug;42:247-254.