Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTMKIK2S)

• DOT Name: Keratin, type II cuticular Hb1 (KRT81)
• Synonyms: Hair keratin K2.9; Keratin, hair, basic, 1; Keratin-81; K81; Metastatic lymph node 137 gene protein; MLN 137; Type II hair keratin Hb1; Type-II keratin Kb21; ghHKb1; ghHb1
• Gene Name: KRT81
• Related Disease:
  Neoplasm
  Breast cancer
  Breast carcinoma
  Ductal breast carcinoma in situ
  Inflammatory breast cancer
  Matthew-Wood syndrome
  Non-small-cell lung cancer
  Plasma cell myeloma
  Advanced cancer
  Asthma
  Lymphoma, non-Hodgkin, familial
  Non-hodgkin lymphoma
  Monilethrix
  Adenocarcinoma
  Lung squamous cell carcinoma
  Squamous cell carcinoma
• UniProt ID: KRT81_HUMAN
• Pfam ID: PF00038 ; PF16208
• Sequence:
  MTCGSGFGGRAFSCISACGPRPGRCCITAAPYRGISCYRGLTGGFGSHSVCGGFRAGSCG
  RSFGYRSGGVCGPSPPCITTVSVNESLLTPLNLEIDPNAQCVKQEEKEQIKSLNSRFAAF
  IDKVRFLEQQNKLLETKLQFYQNRECCQSNLEPLFEGYIETLRREAECVEADSGRLASEL
  NHVQEVLEGYKKKYEEEVSLRATAENEFVALKKDVDCAYLRKSDLEANVEALIQEIDFLR
  RLYEEEILILQSHISDTSVVVKLDNSRDLNMDCIIAEIKAQYDDIVTRSRAEAESWYRSK
  CEEMKATVIRHGETLRRTKEEINELNRMIQRLTAEVENAKCQNSKLEAAVAQSEQQGEAA
  LSDARCKLAELEGALQKAKQDMACLIREYQEVMNSKLGLDIEIATYRRLLEGEEQRLCEG
  IGAVNVCVSSSRGGVVCGDLCVSGSRPVTGSVCSAPCNGNVAVSTGLCAPCGQLNTTCGG
  GSCGVGSCGISSLGVGSCGSSCRKC
• Tissue Specificity: Abundantly expressed in the differentiating cortex of growing (anagen) hair. Expression is restricted to the keratinocytes of the hair cortex and is absent from inner root sheath and medulla. Expressed in malignant lymph node tissue in breast carcinoma tissue.
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Biomarker	[3]
Inflammatory breast cancer	DIS3QRWA	Strong	Genetic Variation	[3]
Matthew-Wood syndrome	DISA7HR7	Strong	Biomarker	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Genetic Variation	[5]
Plasma cell myeloma	DIS0DFZ0	Strong	Genetic Variation	[6]
Advanced cancer	DISAT1Z9	moderate	Genetic Variation	[7]
Asthma	DISW9QNS	moderate	Genetic Variation	[8]
Lymphoma, non-Hodgkin, familial	DISCXYIZ	moderate	Genetic Variation	[7]
Non-hodgkin lymphoma	DISS2Y8A	moderate	Genetic Variation	[7]
Monilethrix	DISF9MNT	Supportive	Autosomal dominant	[9]
Adenocarcinoma	DIS3IHTY	Limited	Biomarker	[10]
Lung squamous cell carcinoma	DISXPIBD	Limited	Biomarker	[10]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Keratin, type II cuticular Hb1 (KRT81).	[11]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Keratin, type II cuticular Hb1 (KRT81).	[12]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Keratin, type II cuticular Hb1 (KRT81).	[13]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Keratin, type II cuticular Hb1 (KRT81).	[14]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Keratin, type II cuticular Hb1 (KRT81).	[15]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Keratin, type II cuticular Hb1 (KRT81).	[16]
Orlistat	DMRJSP8	Approved	Orlistat increases the expression of Keratin, type II cuticular Hb1 (KRT81).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Keratin, type II cuticular Hb1 (KRT81).	[20]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN decreases the expression of Keratin, type II cuticular Hb1 (KRT81).	[21]

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 decreases the methylation of Keratin, type II cuticular Hb1 (KRT81).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Keratin, type II cuticular Hb1 (KRT81).	[19]

References

• [1] A machine learning algorithm predicts molecular subtypes in pancreatic ductal adenocarcinoma with differential response to gemcitabine-based versus FOLFIRINOX chemotherapy.PLoS One. 2019 Oct 2;14(10):e0218642. doi: 10.1371/journal.pone.0218642. eCollection 2019.
• [2] Hair keratin KRT81 is expressed in normal and breast cancer cells and contributes to their invasiveness.Oncol Rep. 2017 May;37(5):2964-2970. doi: 10.3892/or.2017.5564. Epub 2017 Apr 11.
• [3] Gene Expression Differences between Ductal Carcinoma in Situ with and without Progression to Invasive Breast Cancer.Am J Pathol. 2017 Jul;187(7):1648-1655. doi: 10.1016/j.ajpath.2017.03.012.
• [4] Pancreatic Ductal Adenocarcinoma Subtyping Using the Biomarkers Hepatocyte Nuclear Factor-1A and Cytokeratin-81 Correlates with Outcome and Treatment Response.Clin Cancer Res. 2018 Jan 15;24(2):351-359. doi: 10.1158/1078-0432.CCR-17-2180. Epub 2017 Nov 3.
• [5] A genetic variation in microRNA target site of KRT81 gene is associated with survival in early-stage non-small-cell lung cancer.Ann Oncol. 2015 Jun;26(6):1142-1148. doi: 10.1093/annonc/mdv100. Epub 2015 Feb 24.
• [6] Impact of MiRSNPs on survival and progression in patients with multiple myeloma undergoing autologous stem cell transplantation.Clin Cancer Res. 2012 Jul 1;18(13):3697-704. doi: 10.1158/1078-0432.CCR-12-0191. Epub 2012 Apr 26.
• [7] A miR-SNP of the KRT81 gene is associated with the prognosis of non-Hodgkin's lymphoma.Gene. 2014 Apr 15;539(2):198-202. doi: 10.1016/j.gene.2014.02.010. Epub 2014 Feb 12.
• [8] Genome-Wide Association Study Identifies Novel Loci Associated With Diisocyanate-Induced Occupational Asthma.Toxicol Sci. 2015 Jul;146(1):192-201. doi: 10.1093/toxsci/kfv084. Epub 2015 Apr 26.
• [9] A new mutation in the type II hair cortex keratin hHb1 involved in the inherited hair disorder monilethrix. Hum Genet. 1997 Dec;101(2):165-9. doi: 10.1007/s004390050607.
• [10] A dual role for KRT81: a miR-SNP associated with recurrence in non-small-cell lung cancer and a novel marker of squamous cell lung carcinoma.PLoS One. 2011;6(7):e22509. doi: 10.1371/journal.pone.0022509. Epub 2011 Jul 25.
• [11] 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.
• [12] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [13] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [14] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [15] 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.
• [16] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [17] Inhibition of fatty-acid synthase induces caspase-8-mediated tumor cell apoptosis by up-regulating DDIT4. J Biol Chem. 2008 Nov 14;283(46):31378-84. doi: 10.1074/jbc.M803384200. Epub 2008 Sep 16.
• [18] 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.
• [19] 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.
• [20] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [21] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.