Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTKY93H9)

• DOT Name: Caspase-14 (CASP14)
• Synonyms: CASP-14; EC 3.4.22.-
• Gene Name: CASP14
• Related Disease:
  Diabetic retinopathy
  Lung adenocarcinoma
  Atopic dermatitis
  Behcet disease
  Brain neoplasm
  Breast cancer
  Breast carcinoma
  Colon carcinoma
  Colorectal carcinoma
  Dermatitis
  Epithelial neoplasm
  Hepatocellular carcinoma
  leukaemia
  Skin cancer
  Skin neoplasm
  Trichilemmal cyst
  Cervical cancer
  Cervical carcinoma
  Epithelial ovarian cancer
  Ichthyosis, congenital, autosomal recessive 12
  Ovarian cancer
  Ovarian neoplasm
  Advanced cancer
  Colon cancer
  Hypertrichosis
• UniProt ID: CASPE_HUMAN
• EC Number: 3.4.22.-
• Pfam ID: PF00656
• Sequence:
  MSNPRSLEEEKYDMSGARLALILCVTKAREGSEEDLDALEHMFRQLRFESTMKRDPTAEQ
  FQEELEKFQQAIDSREDPVSCAFVVLMAHGREGFLKGEDGEMVKLENLFEALNNKNCQAL
  RAKPKVYIIQACRGEQRDPGETVGGDEIVMVIKDSPQTIPTYTDALHVYSTVEGYIAYRH
  DQKGSCFIQTLVDVFTKRKGHILELLTEVTRRMAEAELVQEGKARKTNPEIQSTLRKRLY
  LQ
• Function: Non-apoptotic caspase involved in epidermal differentiation. Is the predominant caspase in epidermal stratum corneum. Seems to play a role in keratinocyte differentiation and is required for cornification. Regulates maturation of the epidermis by proteolytically processing filaggrin. In vitro has a preference for the substrate [WY]-X-X-D motif and is active on the synthetic caspase substrate WEHD-ACF. Involved in processing of prosaposin in the epidermis. May be involved in retinal pigment epithelium cell barrier function. Involved in DNA degradation in differentiated keratinocytes probably by cleaving DFFA/ICAD leading to liberation of DFFB/CAD.
• Tissue Specificity: Expressed in keratinocytes of adult skin suprabasal layers (from spinous layers to the stratum granulosum and stratum corneum) (at protein level). Expressed in keratinocytes of hair shaft and sebaceous glands (at protein level). In psoriatic skin only expressed at very low levels . The p17/10 mature form is expressed in epidermis stratum corneum, the p20/p8 intermediate form in epidermis upper granular cells of the stratum granulosum .
• Reactome Pathway: Formation of the cornified envelope (R-HSA-6809371)
• BioCyc Pathway: MetaCyc:ENSG00000105141-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Diabetic retinopathy	DISHGUJM	Definitive	Altered Expression	[1]
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[2]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[3]
Behcet disease	DISSYMBS	Strong	Altered Expression	[4]
Brain neoplasm	DISY3EKS	Strong	Genetic Variation	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[6]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[7]
Dermatitis	DISY5SZC	Strong	Biomarker	[3]
Epithelial neoplasm	DIS0T594	Strong	Altered Expression	[8]
Hepatocellular carcinoma	DIS0J828	Strong	Genetic Variation	[7]
leukaemia	DISS7D1V	Strong	Genetic Variation	[9]
Skin cancer	DISTM18U	Strong	Biomarker	[10]
Skin neoplasm	DIS16DDV	Strong	Altered Expression	[10]
Trichilemmal cyst	DISLWEDU	Strong	Biomarker	[11]
Cervical cancer	DISFSHPF	moderate	Biomarker	[12]
Cervical carcinoma	DIST4S00	moderate	Biomarker	[12]
Epithelial ovarian cancer	DIS56MH2	moderate	Altered Expression	[12]
Ichthyosis, congenital, autosomal recessive 12	DISIR5YQ	Moderate	Autosomal recessive	[13]
Ovarian cancer	DISZJHAP	moderate	Altered Expression	[12]
Ovarian neoplasm	DISEAFTY	moderate	Altered Expression	[12]
Advanced cancer	DISAT1Z9	Limited	Altered Expression	[6]
Colon cancer	DISVC52G	Limited	Altered Expression	[6]
Hypertrichosis	DISZUK5W	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Caspase-14 (CASP14).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Caspase-14 (CASP14).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Caspase-14 (CASP14).	[17]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of Caspase-14 (CASP14).	[18]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Caspase-14 (CASP14).	[19]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Caspase-14 (CASP14).	[20]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Caspase-14 (CASP14).	[22]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Caspase-14 (CASP14).	[23]

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 Caspase-14 (CASP14).	[21]

References

• [1] Caspase-14: a novel caspase in the retina with a potential role in diabetic retinopathy.Mol Vis. 2012;18:1895-906. Epub 2012 Jul 14.
• [2] Aberrant expression of caspase 14 in salivary gland carcinomas.J Oral Pathol Med. 2015 Jul;44(6):444-8. doi: 10.1111/jop.12253. Epub 2014 Sep 25.
• [3] Pyrrolidone carboxylic acid levels or caspase-14 expression in the corneocytes of lesional skin correlates with clinical severity, skin barrier function and lesional inflammation in atopic dermatitis.J Dermatol Sci. 2014 Dec;76(3):231-9. doi: 10.1016/j.jdermsci.2014.09.004. Epub 2014 Sep 30.
• [4] Low levels of pannexin-1 in Behet's syndrome.Int J Rheum Dis. 2019 Aug;22(8):1474-1478. doi: 10.1111/1756-185X.13614. Epub 2019 Jun 18.
• [5] Genetic variants of AICDA/CASP14 associated with childhood brain tumor.Genet Mol Res. 2013 Jun 20;12(2):2024-31. doi: 10.4238/2013.January.30.1.
• [6] Caspase14 expression is associated with triple negative phenotypes and cancer stem cell marker expression in breast cancer patients.J Surg Oncol. 2017 Nov;116(6):706-715. doi: 10.1002/jso.24705. Epub 2017 Jun 1.
• [7] Mutational analysis of caspase-14 gene in common carcinomas.Pathology. 2007 Jun;39(3):330-3. doi: 10.1080/00313020701329815.
• [8] Aberrant expression of caspase-14 in epithelial tumors.Biochem Biophys Res Commun. 2005 Sep 23;335(2):309-13. doi: 10.1016/j.bbrc.2005.07.072.
• [9] Association between CASP7 and CASP14 genetic polymorphisms and the risk of childhood leukemia.Hum Immunol. 2012 Jul;73(7):736-9. doi: 10.1016/j.humimm.2012.04.017. Epub 2012 Apr 28.
• [10] Expression of caspase-14 reduces tumorigenicity of skin cancer cells.In Vivo. 2007 Mar-Apr;21(2):279-83.
• [11] Comparative immunohistochemical analyses on the modes of cell death/keratinization in epidermal cyst, trichilemmal cyst, and pilomatricoma.Am J Dermatopathol. 2011 Feb;33(1):78-83. doi: 10.1097/DAD.0b013e3181e3aec1.
• [12] Tumor-associated alterations in caspase-14 expression in epithelial malignancies.Clin Cancer Res. 2005 Aug 1;11(15):5462-71. doi: 10.1158/1078-0432.CCR-04-2527.
• [13] Whole-Exome-Sequencing Reveals Small Deletions in CASP14 in Patients with Autosomal Recessive Inherited Ichthyosis. Acta Derm Venereol. 2017 Jan 4;97(1):102-104. doi: 10.2340/00015555-2510.
• [14] A case of microdeletion of 19p13 with intellectual disability, hypertrichosis, synophrys, and protruding front teeth.Eur J Med Genet. 2012 Oct;55(10):564-7. doi: 10.1016/j.ejmg.2012.06.009. Epub 2012 Jun 30.
• [15] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [16] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [17] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [18] Effect of zoledronic acid on oral fibroblasts and epithelial cells: a potential mechanism of bisphosphonate-associated osteonecrosis. Br J Haematol. 2009 Mar;144(5):667-76. doi: 10.1111/j.1365-2141.2008.07504.x. Epub 2008 Nov 20.
• [19] Characterizing the genetic basis for nicotine induced cancer development: a transcriptome sequencing study. PLoS One. 2013 Jun 18;8(6):e67252.
• [20] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [21] 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.
• [22] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [23] Asian dust storm particles induce a broad toxicological transcriptional program in human epidermal keratinocytes. Toxicol Lett. 2011 Jan 15;200(1-2):92-9.