Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXXM8EH)

• DOT Name: Cystatin-S (CST4)
• Synonyms: Cystatin-4; Cystatin-SA-III; Salivary acidic protein 1
• Gene Name: CST4
• Related Disease:
  Peeling skin syndrome 1
  Potocki-Shaffer syndrome
  Systemic sclerosis
  Bacterial vaginosis
  Colorectal carcinoma
  Keratoconus
  Xerophthalmia
  Asthma
  Gastric cancer
  Stomach cancer
• UniProt ID: CYTS_HUMAN
• Pfam ID: PF00031
• Sequence:
  MARPLCTLLLLMATLAGALASSSKEENRIIPGGIYDADLNDEWVQRALHFAISEYNKATE
  DEYYRRPLQVLRAREQTFGGVNYFFDVEVGRTICTKSQPNLDTCAFHEQPELQKKQLCSF
  EIYEVPWEDRMSLVNSRCQEA
• Function: This protein strongly inhibits papain and ficin, partially inhibits stem bromelain and bovine cathepsin C, but does not inhibit porcine cathepsin B or clostripain. Papain is inhibited non-competitively.
• Tissue Specificity: Expressed in submandibular and sublingual saliva but not in parotid saliva (at protein level). Expressed in saliva, tears, urine and seminal fluid.
• KEGG Pathway: Salivary secretion (hsa04970)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Peeling skin syndrome 1	DIS35574	Definitive	Altered Expression	[1]
Potocki-Shaffer syndrome	DISKGU59	Definitive	Altered Expression	[1]
Systemic sclerosis	DISF44L6	Definitive	Altered Expression	[1]
Bacterial vaginosis	DISK2MZ2	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[3]
Keratoconus	DISOONXH	Strong	Biomarker	[4]
Xerophthalmia	DIS5B72B	Strong	Biomarker	[4]
Asthma	DISW9QNS	moderate	Altered Expression	[5]
Gastric cancer	DISXGOUK	moderate	Biomarker	[3]
Stomach cancer	DISKIJSX	moderate	Biomarker	[3]

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 Cystatin-S (CST4).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cystatin-S (CST4).	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Cystatin-S (CST4).	[7]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Cystatin-S (CST4).	[8]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Cystatin-S (CST4).	[10]

References

• [1] Cystatin S-a candidate biomarker for severity of submandibular gland involvement in Sjgren's syndrome.Rheumatology (Oxford). 2017 Jun 1;56(6):1031-1038. doi: 10.1093/rheumatology/kew501.
• [2] Characterization of cervico-vaginal microbiota in women developing persistent high-risk Human Papillomavirus infection.Sci Rep. 2017 Aug 31;7(1):10200. doi: 10.1038/s41598-017-09842-6.
• [3] Antibody-sandwich ELISA analysis of a novel blood biomarker of CST4 in gastrointestinal cancers.Onco Targets Ther. 2018 Mar 28;11:1743-1756. doi: 10.2147/OTT.S149204. eCollection 2018.
• [4] Changes in tear biomarker levels in keratoconus after corneal collagen crosslinking.Mol Vis. 2019 Jan 20;25:12-21. eCollection 2019.
• [5] Multitissue Transcriptomics Delineates the Diversity of Airway T Cell Functions in Asthma.Am J Respir Cell Mol Biol. 2018 Feb;58(2):261-270. doi: 10.1165/rcmb.2017-0162OC.
• [6] 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.
• [7] The effect of DNA methylation inhibitor 5-Aza-2'-deoxycytidine on human endometrial stromal cells. Hum Reprod. 2010 Nov;25(11):2859-69.
• [8] Resveratrol inhibits pancreatic cancer cell proliferation through transcriptional induction of macrophage inhibitory cytokine-1. J Surg Res. 2007 Apr;138(2):163-9. doi: 10.1016/j.jss.2006.05.037. Epub 2007 Jan 25.
• [9] 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.
• [10] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.