Details of Drug Off-Target (DOT)

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

• DOT Name: Keratin, type II cytoskeletal 6B (KRT6B)
• Synonyms: Cytokeratin-6B; CK-6B; Keratin-6B; K6B; Type-II keratin Kb10
• Gene Name: KRT6B
• Related Disease:
  Autosomal dominant polycystic kidney disease
  Colorectal carcinoma
  Non-small-cell lung cancer
  Pachyonychia congenita 4
  Pheochromocytoma
  Sjogren syndrome
  Squamous cell carcinoma
  Bladder cancer
  Neoplasm
  Pachyonychia congenita 2
  Urinary bladder cancer
  Urinary bladder neoplasm
  Pachyonychia congenita
  Lung adenocarcinoma
  Dental caries
• UniProt ID: K2C6B_HUMAN
• Pfam ID: PF00038 ; PF16208
• Sequence:
  MASTSTTIRSHSSSRRGFSANSARLPGVSRSGFSSISVSRSRGSGGLGGACGGAGFGSRS
  LYGLGGSKRISIGGGSCAISGGYGSRAGGSYGFGGAGSGFGFGGGAGIGFGLGGGAGLAG
  GFGGPGFPVCPPGGIQEVTVNQSLLTPLNLQIDPAIQRVRAEEREQIKTLNNKFASFIDK
  VRFLEQQNKVLDTKWTLLQEQGTKTVRQNLEPLFEQYINNLRRQLDNIVGERGRLDSELR
  NMQDLVEDLKNKYEDEINKRTAAENEFVTLKKDVDAAYMNKVELQAKADTLTDEINFLRA
  LYDAELSQMQTHISDTSVVLSMDNNRNLDLDSIIAEVKAQYEEIAQRSRAEAESWYQTKY
  EELQITAGRHGDDLRNTKQEIAEINRMIQRLRSEIDHVKKQCANLQAAIADAEQRGEMAL
  KDAKNKLEGLEDALQKAKQDLARLLKEYQELMNVKLALDVEIATYRKLLEGEECRLNGEG
  VGQVNISVVQSTVSSGYGGASGVGSGLGLGGGSSYSYGSGLGVGGGFSSSSGRATGGGLS
  SVGGGSSTIKYTTTSSSSRKSYKH
• Tissue Specificity: Constitutively expressed in distinct types of epithelia such as those in oral mucosa, esophagus, papillae of tongue and hair follicle outer root sheath.
• Reactome Pathway:
  Formation of the cornified envelope (R-HSA-6809371)
  Keratinization (R-HSA-6805567)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Autosomal dominant polycystic kidney disease	DISBHWUI	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[2]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[3]
Pachyonychia congenita 4	DIS0AY06	Strong	Autosomal dominant	[4]
Pheochromocytoma	DIS56IFV	Strong	Altered Expression	[5]
Sjogren syndrome	DISUBX7H	Strong	Biomarker	[6]
Squamous cell carcinoma	DISQVIFL	Strong	Biomarker	[7]
Bladder cancer	DISUHNM0	moderate	Altered Expression	[8]
Neoplasm	DISZKGEW	moderate	Altered Expression	[8]
Pachyonychia congenita 2	DISN77SX	moderate	Genetic Variation	[9]
Urinary bladder cancer	DISDV4T7	moderate	Altered Expression	[8]
Urinary bladder neoplasm	DIS7HACE	moderate	Altered Expression	[8]
Pachyonychia congenita	DISW8VPN	Supportive	Autosomal dominant	[10]
Lung adenocarcinoma	DISD51WR	Disputed	Biomarker	[7]
Dental caries	DISRBCMD	Limited	Genetic Variation	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Keratin, type II cytoskeletal 6B (KRT6B).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Keratin, type II cytoskeletal 6B (KRT6B).	[13]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Keratin, type II cytoskeletal 6B (KRT6B).	[14]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Keratin, type II cytoskeletal 6B (KRT6B).	[15]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Keratin, type II cytoskeletal 6B (KRT6B).	[16]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Keratin, type II cytoskeletal 6B (KRT6B).	[19]
PD-153035	DM7KJTI	Discontinued in Phase 1	PD-153035 affects the expression of Keratin, type II cytoskeletal 6B (KRT6B).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Keratin, type II cytoskeletal 6B (KRT6B).	[20]

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 6B (KRT6B).	[17]

1 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 affects the methylation of Keratin, type II cytoskeletal 6B (KRT6B).	[18]

References

• [1] Phosphorylation, protein kinases and ADPKD.Biochim Biophys Acta. 2011 Oct;1812(10):1219-24. doi: 10.1016/j.bbadis.2011.03.001. Epub 2011 Mar 15.
• [2] Polycystin-1 and polycystin-2 are involved in the acquisition of aggressive phenotypes in colorectal cancer.Int J Cancer. 2015 Apr 1;136(7):1515-27. doi: 10.1002/ijc.29140. Epub 2014 Sep 3.
• [3] Human positive coactivator 4 is a potential novel therapeutic target in non-small cell lung cancer.Cancer Gene Ther. 2012 Oct;19(10):690-6. doi: 10.1038/cgt.2012.52. Epub 2012 Aug 24.
• [4] 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.
• [5] Differential expression and processing of secretogranin II in relation to the status of pheochromocytoma: implications for the production of the tumoral marker EM66.J Mol Endocrinol. 2012 Feb 6;48(2):115-27. doi: 10.1530/JME-11-0077. Print 2012 Apr.
• [6] Up-regulated gene expression in the conjunctival epithelium of patients with Sjgren's syndrome.Exp Eye Res. 2003 Jul;77(1):17-26. doi: 10.1016/s0014-4835(03)00087-3.
• [7] Eight potential biomarkers for distinguishing between lung adenocarcinoma and squamous cell carcinoma.Oncotarget. 2017 May 3;8(42):71759-71771. doi: 10.18632/oncotarget.17606. eCollection 2017 Sep 22.
• [8] Enhanced metastatic potential in the MB49 urothelial carcinoma model.Sci Rep. 2019 May 15;9(1):7425. doi: 10.1038/s41598-019-43641-5.
• [9] Keratin 17 mutation in pachyonychia congenita type 2 patient with early onset steatocystoma multiplex and Hutchinson-like tooth deformity.J Dermatol. 2006 Mar;33(3):161-4. doi: 10.1111/j.1346-8138.2006.00037.x.
• [10] 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.
• [11] Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay.PLoS Genet. 2018 Jan 22;14(1):e1007168. doi: 10.1371/journal.pgen.1007168. eCollection 2018 Jan.
• [12] 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.
• [13] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [14] Progesterone regulation of implantation-related genes: new insights into the role of oestrogen. Cell Mol Life Sci. 2007 Apr;64(7-8):1009-32.
• [15] 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.
• [16] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [17] 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.
• [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] CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
• [20] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.