Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTS6WLF7)

• DOT Name: Keratin, type I cytoskeletal 15 (KRT15)
• Synonyms: Cytokeratin-15; CK-15; Keratin-15; K15
• Gene Name: KRT15
• Related Disease:
  Adenocarcinoma
  Adenoma
  Advanced cancer
  Basal cell carcinoma
  Benign prostatic hyperplasia
  Breast carcinoma
  Carcinoma
  Ductal breast carcinoma in situ
  Gastric cancer
  Intestinal cancer
  Kaposi sarcoma
  Melanoma
  Oral lichen planus
  Polymyalgia rheumatica
  Skin neoplasm
  Stomach cancer
  Acute graft versus host disease
  Alopecia
  Graft-versus-host disease
  Urinary bladder cancer
  Aplasia cutis congenita
  Corpus callosum, agenesis of
  Squamous cell carcinoma
• UniProt ID: K1C15_HUMAN
• Pfam ID: PF00038
• Sequence:
  MTTTFLQTSSSTFGGGSTRGGSLLAGGGGFGGGSLSGGGGSRSISASSARFVSSGSGGGY
  GGGMRVCGFGGGAGSVFGGGFGGGVGGGFGGGFGGGDGGLLSGNEKITMQNLNDRLASYL
  DKVRALEEANADLEVKIHDWYQKQTPTSPECDYSQYFKTIEELRDKIMATTIDNSRVILE
  IDNARLAADDFRLKYENELALRQGVEADINGLRRVLDELTLARTDLEMQIEGLNEELAYL
  KKNHEEEMKEFSSQLAGQVNVEMDAAPGVDLTRVLAEMREQYEAMAEKNRRDVEAWFFSK
  TEELNKEVASNTEMIQTSKTEITDLRRTMQELEIELQSQLSMKAGLENSLAETECRYATQ
  LQQIQGLIGGLEAQLSELRCEMEAQNQEYKMLLDIKTRLEQEIATYRSLLEGQDAKMAGI
  AIREASSGGGGSSSNFHINVEESVDGQVVSSHKREI
• Tissue Specificity: Expressed in a discontinuous manner in the basal cell layer of adult skin epidermis, but continuously in the basal layer of fetal skin epidermis and nail. Also expressed in the outer root sheath above the hair bulb in hair follicle (at protein level). Expressed homogeneously in all cell layers of the esophagus and exocervix, but detected in the basal cell layer only of oral mucosa, skin and in the basal plus the next two layers of the suprabasal epithelium of the palate.
• KEGG Pathway:
  Estrogen sig.ling pathway (hsa04915)
  Staphylococcus aureus infection (hsa05150)
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Biomarker	[1]
Adenoma	DIS78ZEV	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Basal cell carcinoma	DIS7PYN3	Strong	Altered Expression	[4]
Benign prostatic hyperplasia	DISI3CW2	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Carcinoma	DISH9F1N	Strong	Altered Expression	[7]
Ductal breast carcinoma in situ	DISLCJY7	Strong	Altered Expression	[6]
Gastric cancer	DISXGOUK	Strong	Biomarker	[8]
Intestinal cancer	DISYCNF1	Strong	Biomarker	[2]
Kaposi sarcoma	DISC1H1Z	Strong	Altered Expression	[9]
Melanoma	DIS1RRCY	Strong	Biomarker	[10]
Oral lichen planus	DISVEAJA	Strong	Biomarker	[10]
Polymyalgia rheumatica	DIS5F36E	Strong	Biomarker	[11]
Skin neoplasm	DIS16DDV	Strong	Biomarker	[12]
Stomach cancer	DISKIJSX	Strong	Biomarker	[8]
Acute graft versus host disease	DIS8KLVM	moderate	Altered Expression	[13]
Alopecia	DIS37HU4	moderate	Biomarker	[14]
Graft-versus-host disease	DIS0QADF	moderate	Biomarker	[13]
Urinary bladder cancer	DISDV4T7	moderate	Altered Expression	[7]
Aplasia cutis congenita	DISMDAYM	Limited	Biomarker	[15]
Corpus callosum, agenesis of	DISO9P40	Limited	Biomarker	[15]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[16]

1 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 I cytoskeletal 15 (KRT15).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[18]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[19]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[20]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[21]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Keratin, type I cytoskeletal 15 (KRT15).	[22]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[23]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[24]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Keratin, type I cytoskeletal 15 (KRT15).	[25]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[26]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[27]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[19]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[28]
Cidofovir	DMA13GD	Approved	Cidofovir increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[27]
Simvastatin	DM30SGU	Approved	Simvastatin increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[29]
Ifosfamide	DMCT3I8	Approved	Ifosfamide increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[27]
Alitretinoin	DMME8LH	Approved	Alitretinoin increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[19]
Adefovir dipivoxil	DMMAWY1	Approved	Adefovir dipivoxil increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[27]
Bexarotene	DMOBIKY	Approved	Bexarotene increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[30]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[31]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[32]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[34]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[35]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[36]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid increases the expression of Keratin, type I cytoskeletal 15 (KRT15).	[19]

References

• [1] The value of desmosomal plaque-related markers to distinguish squamous cell carcinoma and adenocarcinoma of the lung.Ups J Med Sci. 2020 Feb;125(1):19-29. doi: 10.1080/03009734.2019.1692101. Epub 2019 Dec 6.
• [2] Mouse Intestinal Krt15+ Crypt Cells Are Radio-Resistant and Tumor Initiating.Stem Cell Reports. 2018 Jun 5;10(6):1947-1958. doi: 10.1016/j.stemcr.2018.04.022. Epub 2018 May 24.
• [3] Aberrant cytokeratin expression during arsenic-induced acquired malignant phenotype in human HaCaT keratinocytes consistent with epidermal carcinogenesis.Toxicology. 2009 Aug 3;262(2):162-70. doi: 10.1016/j.tox.2009.06.003. Epub 2009 Jun 12.
• [4] Elastic fiber staining and cytokeratin 15 expression pattern in trichoepithelioma and basal cell carcinoma.J Dermatol. 2008 Aug;35(8):499-502. doi: 10.1111/j.1346-8138.2008.00510.x.
• [5] Molecular analyses of prostate tumors for diagnosis of malignancy on fine-needle aspiration biopsies.Oncotarget. 2017 Nov 6;8(62):104761-104771. doi: 10.18632/oncotarget.22289. eCollection 2017 Dec 1.
• [6] Identification of a subset of breast carcinomas characterized by expression of cytokeratin 15: relationship between CK15+ progenitor/amplified cells and pre-malignant lesions and invasive disease.Mol Oncol. 2007 Dec;1(3):321-49. doi: 10.1016/j.molonc.2007.09.004. Epub 2007 Sep 25.
• [7] Cytokeratin 15 marks basal epithelia in developing ureters and is upregulated in a subset of urothelial cell carcinomas.PLoS One. 2013 Nov 18;8(11):e81167. doi: 10.1371/journal.pone.0081167. eCollection 2013.
• [8] KRT15, INHBA, MATN3, and AGT are aberrantly methylated and differentially expressed in gastric cancer and associated with prognosis.Pathol Res Pract. 2019 May;215(5):893-899. doi: 10.1016/j.prp.2019.01.034. Epub 2019 Jan 28.
• [9] The Kaposi's sarcoma-associated herpesvirus (KSHV) non-structural membrane protein K15 is required for viral lytic replication and may represent a therapeutic target.PLoS Pathog. 2017 Sep 22;13(9):e1006639. doi: 10.1371/journal.ppat.1006639. eCollection 2017 Sep.
• [10] Lichen planus: molecular pathway and clinical implications in oral disorders.J Biol Regul Homeost Agents. 2018 Jan-Feb;32(2 Suppl. 1):135-138.
• [11] Analysis of the B cell repertoire against autoantigens in patients with giant cell arteritis and polymyalgia rheumatica.Clin Exp Immunol. 2002 Feb;127(2):379-85. doi: 10.1046/j.1365-2249.2002.01751.x.
• [12] A keratin 15 containing stem cell population from the hair follicle contributes to squamous papilloma development in the mouse.Mol Carcinog. 2013 Oct;52(10):751-9. doi: 10.1002/mc.21896. Epub 2012 Mar 16.
• [13] Graft-versus-host disease-related cytokine-driven apoptosis depends on p73 in cytokeratin 15-positive target cells.Biol Blood Marrow Transplant. 2012 Jun;18(6):841-51. doi: 10.1016/j.bbmt.2012.02.004. Epub 2012 Mar 30.
• [14] Preclinical evidence that the PPAR modulator, N-Acetyl-GED-0507-34-Levo, may protect human hair follicle epithelial stem cells against lichen planopilaris-associated damage.J Eur Acad Dermatol Venereol. 2020 Apr;34(4):e195-e197. doi: 10.1111/jdv.16114. Epub 2020 Feb 5.
• [15] Detection of MYB Alterations and Other Immunohistochemical Markers in Primary Cutaneous Adenoid Cystic Carcinoma.Am J Surg Pathol. 2015 Oct;39(10):1347-56. doi: 10.1097/PAS.0000000000000463.
• [16] Macrophages Promote Growth of Squamous Cancer Independent of T cells.J Dent Res. 2019 Jul;98(8):896-903. doi: 10.1177/0022034519854734. Epub 2019 Jun 12.
• [17] 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.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] 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.
• [20] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [21] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [22] 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.
• [23] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [24] 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.
• [25] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [26] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [27] Transcriptomics hit the target: monitoring of ligand-activated and stress response pathways for chemical testing. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):7-18.
• [28] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [29] Simvastatin inactivates beta1-integrin and extracellular signal-related kinase signaling and inhibits cell proliferation in head and neck squamous cell carcinoma cells. Cancer Sci. 2007 Jun;98(6):890-9.
• [30] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [31] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [32] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [33] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [34] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
• [35] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [36] Transcriptomic alterations induced by Ochratoxin A in rat and human renal proximal tubular in vitro models and comparison to a rat in vivo model. Arch Toxicol. 2012 Apr;86(4):571-89.