Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT28B9E6)

• DOT Name: Keratin, type II cytoskeletal 75 (KRT75)
• Synonyms: Cytokeratin-75; CK-75; Keratin-6 hair follicle; hK6hf; Keratin-75; K75; Type II keratin-K6hf; Type-II keratin Kb18
• Gene Name: KRT75
• Related Disease:
  Ependymoma
  Dental caries
  Hyperplasia
  Neoplasm
  Loose anagen syndrome
• UniProt ID: K2C75_HUMAN
• Pfam ID: PF00038 ; PF16208
• Sequence:
  MSRQSSITFQSGSRRGFSTTSAITPAAGRSRFSSVSVARSAAGSGGLGRISSAGASFGSR
  SLYNLGGAKRVSINGCGSSCRSGFGGRASNRFGVNSGFGYGGGVGGGFSGPSFPVCPPGG
  IQEVTVNQSLLTPLHLQIDPTIQRVRAEEREQIKTLNNKFASFIDKVRFLEQQNKVLETK
  WALLQEQGSRTVRQNLEPLFDSYTSELRRQLESITTERGRLEAELRNMQDVVEDFKVRYE
  DEINKRTAAENEFVALKKDVDAAYMNKVELEAKVKSLPEEINFIHSVFDAELSQLQTQVG
  DTSVVLSMDNNRNLDLDSIIAEVKAQYEDIANRSRAEAESWYQTKYEELQVTAGRHGDDL
  RNTKQEISEMNRMIQRLRAEIDSVKKQCSSLQTAIADAEQRGELALKDARAKLVDLEEAL
  QKAKQDMARLLREYQELMNIKLALDVEIATYRKLLEGEECRLSGEGVSPVNISVVTSTLS
  SGYGSGSSIGGGNLGLGGGSGYSFTTSGGHSLGAGLGGSGFSATSNRGLGGSGSSVKFVS
  TTSSSQKSYTH
• Function: Plays a central role in hair and nail formation. Essential component of keratin intermediate filaments in the companion layer of the hair follicle.
• Tissue Specificity: Highly expressed in hair follicles from scalp. Specifically expressed in the of the hair companion layer follicle, a single layered band of flat and vertically oriented cells between the cuboidal outer root sheath (ORS) cells and the inner root sheath (IRS) that stretches from the lowermost bulb region to the isthmus of the follicle. Also expressed in medullated hairs. In nails, it is almost exclusively present in the nail bed (at protein level).
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ependymoma	DISUMRNZ	Definitive	Biomarker	[1]
Dental caries	DISRBCMD	Strong	Genetic Variation	[2]
Hyperplasia	DISK4DFB	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[1]
Loose anagen syndrome	DISJVGFD	Limited	Genetic Variation	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Keratin, type II cytoskeletal 75 (KRT75).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Keratin, type II cytoskeletal 75 (KRT75).	[6]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Keratin, type II cytoskeletal 75 (KRT75).	[7]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of Keratin, type II cytoskeletal 75 (KRT75).	[5]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Keratin, type II cytoskeletal 75 (KRT75).	[5]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Keratin, type II cytoskeletal 75 (KRT75).	[11]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Keratin, type II cytoskeletal 75 (KRT75).	[5]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Keratin, type II cytoskeletal 75 (KRT75).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Keratin, type II cytoskeletal 75 (KRT75).	[10]

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 75 (KRT75).	[9]

References

• [1] Molecular characterization of histopathological ependymoma variants.Acta Neuropathol. 2020 Feb;139(2):305-318. doi: 10.1007/s00401-019-02090-0. Epub 2019 Nov 2.
• [2] Keratins as components of the enamel organic matrix.Matrix Biol. 2016 May-Jul;52-54:260-265. doi: 10.1016/j.matbio.2015.12.007. Epub 2015 Dec 17.
• [3] The role of cytokeratin 5/6 as an adjunct diagnostic tool in breast core needle biopsies.Int J Surg Pathol. 2008 Oct;16(4):399-406. doi: 10.1177/1066896908316901. Epub 2008 May 21.
• [4] Is the loose anagen hair syndrome a keratin disorder? A clinical and molecular study.Arch Dermatol. 2002 Apr;138(4):501-6. doi: 10.1001/archderm.138.4.501.
• [5] 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.
• [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] Estradiol and selective estrogen receptor modulators differentially regulate target genes with estrogen receptors alpha and beta. Mol Biol Cell. 2004 Mar;15(3):1262-72. doi: 10.1091/mbc.e03-06-0360. Epub 2003 Dec 29.
• [8] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [9] 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.
• [10] 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.
• [11] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.