Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAU54U3)

• DOT Name: Keratin, type II cytoskeletal 80 (KRT80)
• Synonyms: Cytokeratin-80; CK-80; Keratin-80; K80; Type-II keratin Kb20
• Gene Name: KRT80
• Related Disease:
  Advanced cancer
  Pachyonychia congenita
  Breast cancer
  Breast carcinoma
  Colorectal carcinoma
  Monilethrix
  Neoplasm
• UniProt ID: K2C80_HUMAN
• Pfam ID: PF00038
• Sequence:
  MACRSCVVGFSSLSSCEVTPVGSPRPGTSGWDSCRAPGPGFSSRSLTGCWSAGTISKVTV
  NPGLLVPLDVKLDPAVQQLKNQEKEEMKALNDKFASLIGKVQALEQRNQLLETRWSFLQG
  QDSAIFDLGHLYEEYQGRLQEELRKVSQERGQLEANLLQVLEKVEEFRIRYEDEISKRTD
  MEFTFVQLKKDLDAECLHRTELETKLKSLESFVELMKTIYEQELKDLAAQVKDVSVTVGM
  DSRCHIDLSGIVEEVKAQYDAVAARSLEEAEAYSRSQLEEQAARSAEYGSSLQSSRSEIA
  DLNVRIQKLRSQILSVKSHCLKLEENIKTAEEQGELAFQDAKTKLAQLEAALQQAKQDMA
  RQLRKYQELMNVKLALDIEIATYRKLVEGEEGRMDSPSATVVSAVQSRCKTAASRSGLSK
  APSRKKKGSKGPVIKITEMSEKYFSQESEVSE
• Tissue Specificity: Weakly expressed in tongue, but not skin or in any other tissues or organs examined.
• 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
Advanced cancer	DISAT1Z9	Definitive	Altered Expression	[1]
Pachyonychia congenita	DISW8VPN	Definitive	Biomarker	[2]
Breast cancer	DIS7DPX1	Strong	Biomarker	[1]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Monilethrix	DISF9MNT	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]

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 80 (KRT80).	[5]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid decreases the phosphorylation of Keratin, type II cytoskeletal 80 (KRT80).	[23]

20 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 80 (KRT80).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[9]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[10]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[11]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[12]
Etoposide	DMNH3PG	Approved	Etoposide increases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[13]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[14]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate decreases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[15]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide increases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[13]
Dactinomycin	DM2YGNW	Approved	Dactinomycin increases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[19]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[21]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Keratin, type II cytoskeletal 80 (KRT80).	[22]

References

• [1] SREBP1 drives Keratin-80-dependent cytoskeletal changes and invasive behavior in endocrine-resistant ER breast cancer.Nat Commun. 2019 May 9;10(1):2115. doi: 10.1038/s41467-019-09676-y.
• [2] Mutation of a type II keratin gene (K6a) in pachyonychia congenita.Nat Genet. 1995 Jul;10(3):363-5. doi: 10.1038/ng0795-363.
• [3] Keratin 80 promotes migration and invasion of colorectal carcinoma by interacting with PRKDC via activating the AKT pathway.Cell Death Dis. 2018 Sep 27;9(10):1009. doi: 10.1038/s41419-018-1030-y.
• [4] Mutations in the hair cortex keratin hHb6 cause the inherited hair disease monilethrix. Nat Genet. 1997 Aug;16(4):372-4. doi: 10.1038/ng0897-372.
• [5] 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.
• [6] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [12] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [13] Genomic profiling uncovers a molecular pattern for toxicological characterization of mutagens and promutagens in vitro. Toxicol Sci. 2011 Jul;122(1):185-97.
• [14] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [15] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [16] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [17] 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.
• [18] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [19] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [20] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [21] 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.
• [22] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [23] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.