Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT392M5T)

• DOT Name: Keratin, type II cytoskeletal 6A (KRT6A)
• Synonyms: Cytokeratin-6A; CK-6A; Cytokeratin-6D; CK-6D; Keratin-6A; K6A; Type-II keratin Kb6; allergen Hom s 5
• Gene Name: KRT6A
• Related Disease:
  Pachyonychia congenita 3
  Pachyonychia congenita
• UniProt ID: K2C6A_HUMAN
• PDB ID: 5KI0
• Pfam ID: PF00038 ; PF16208
• Sequence:
  MASTSTTIRSHSSSRRGFSANSARLPGVSRSGFSSVSVSRSRGSGGLGGACGGAGFGSRS
  LYGLGGSKRISIGGGSCAISGGYGSRAGGSYGFGGAGSGFGFGGGAGIGFGLGGGAGLAG
  GFGGPGFPVCPPGGIQEVTVNQSLLTPLNLQIDPTIQRVRAEEREQIKTLNNKFASFIDK
  VRFLEQQNKVLETKWTLLQEQGTKTVRQNLEPLFEQYINNLRRQLDSIVGERGRLDSELR
  GMQDLVEDFKNKYEDEINKRTAAENEFVTLKKDVDAAYMNKVELQAKADTLTDEINFLRA
  LYDAELSQMQTHISDTSVVLSMDNNRNLDLDSIIAEVKAQYEEIAQRSRAEAESWYQTKY
  EELQVTAGRHGDDLRNTKQEIAEINRMIQRLRSEIDHVKKQCANLQAAIADAEQRGEMAL
  KDAKNKLEGLEDALQKAKQDLARLLKEYQELMNVKLALDVEIATYRKLLEGEECRLNGEG
  VGQVNISVVQSTVSSGYGGASGVGSGLGLGGGSSYSYGSGLGVGGGFSSSSGRAIGGGLS
  SVGGGSSTIKYTTTSSSSRKSYKH
• Function: Epidermis-specific type I keratin involved in wound healing. Involved in the activation of follicular keratinocytes after wounding, while it does not play a major role in keratinocyte proliferation or migration. Participates in the regulation of epithelial migration by inhibiting the activity of SRC during wound repair.
• Tissue Specificity: Expressed in the corneal epithelium (at protein level).
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Pachyonychia congenita 3	DISZLC6C	Strong	Autosomal dominant	[1]
Pachyonychia congenita	DISW8VPN	Supportive	Autosomal dominant	[2]

16 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 6A (KRT6A).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[4]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[6]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[8]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[9]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[10]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[4]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[11]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[4]
Pioglitazone	DMKJ485	Approved	Pioglitazone decreases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[12]
PD-153035	DM7KJTI	Discontinued in Phase 1	PD-153035 decreases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[11]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[15]
chloropicrin	DMSGBQA	Investigative	chloropicrin affects the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[17]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Keratin, type II cytoskeletal 6A (KRT6A).	[4]

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 6A (KRT6A).	[13]

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 increases the methylation of Keratin, type II cytoskeletal 6A (KRT6A).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Keratin, type II cytoskeletal 6A (KRT6A).	[16]

References

• [1] 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.
• [2] Pachyonychia Congenita. 2006 Jan 27 [updated 2017 Nov 30]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [3] 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.
• [4] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [5] 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.
• [6] Transformation of human urothelial cells (UROtsa) by as and cd induces the expression of keratin 6a. Environ Health Perspect. 2008 Apr;116(4):434-40. doi: 10.1289/ehp.10279.
• [7] Detection of gene expression alteration of myeloma cells treated with arsenic trioxide. Zhonghua Xue Ye Xue Za Zhi. 2005 Apr;26(4):209-13.
• [8] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [10] 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.
• [11] 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.
• [12] Peroxisome proliferator activated receptor gamma (PPAR-gama) ligand pioglitazone regulated gene networks in term human primary trophoblast cells. Reprod Toxicol. 2018 Oct;81:99-107.
• [13] 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.
• [14] 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.
• [15] Proteomic signatures in thapsigargin-treated hepatoma cells. Chem Res Toxicol. 2011 Aug 15;24(8):1215-22. doi: 10.1021/tx200109y. Epub 2011 Jul 1.
• [16] 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.
• [17] Transcriptomic analysis of human primary bronchial epithelial cells after chloropicrin treatment. Chem Res Toxicol. 2015 Oct 19;28(10):1926-35.