Details of Drug Off-Target (DOT)

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

• DOT Name: Cystatin-D (CST5)
• Synonyms: Cystatin-5
• Gene Name: CST5
• Related Disease:
  Colon cancer
  Colon carcinoma
  Head-neck squamous cell carcinoma
  Neoplasm
  Osteoporosis
  Ovarian cancer
• UniProt ID: CYTD_HUMAN
• PDB ID: 1RN7; 1ROA
• Pfam ID: PF00031
• Sequence:
  MMWPMHTPLLLLTALMVAVAGSASAQSRTLAGGIHATDLNDKSVQCALDFAISEYNKVIN
  KDEYYSRPLQVMAAYQQIVGGVNYYFNVKFGRTTCTKSQPNLDNCPFNDQPKLKEEEFCS
  FQINEVPWEDKISILNYKCRKV
• Function: Cysteine proteinase inhibitor that possibly plays a protective role against proteinases present in the oral cavity. The order of preference for inhibition is cathepsin S > cathepsin H > cathepsin L > cathepsin B.
• Tissue Specificity: Expressed in submandibular and sublingual saliva but not in parotid saliva (at protein level). Expressed in parotid gland but not in seminal vesicle, prostate, epididymis, testis, ovary, placenta, thyroid, gastric corpus, small intestine, liver, or gall bladder tissue.
• KEGG Pathway: Salivary secretion (hsa04970)

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon cancer	DISVC52G	Strong	Biomarker	[1]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[1]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[2]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Osteoporosis	DISF2JE0	Strong	Altered Expression	[3]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
NAPQI	DM8F5LR	Investigative	Cystatin-D (CST5) affects the response to substance of NAPQI.	[10]

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-D (CST5).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cystatin-D (CST5).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Cystatin-D (CST5).	[6]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Cystatin-D (CST5).	[7]
MG-132	DMKA2YS	Preclinical	MG-132 decreases the expression of Cystatin-D (CST5).	[9]

References

• [1] Cystatin D locates in the nucleus at sites of active transcription and modulates gene and protein expression.J Biol Chem. 2015 Oct 30;290(44):26533-48. doi: 10.1074/jbc.M115.660175. Epub 2015 Sep 13.
• [2] Cysteine proteinase inhibitor cystatin C in squamous cell carcinoma of the head and neck: relation to prognosis.Br J Cancer. 2004 May 17;90(10):1961-8. doi: 10.1038/sj.bjc.6601830.
• [3] Up-regulated CST5 inhibits bone resorption and activation of osteoclasts in rat models of osteoporosis via suppression of the NF-B pathway.J Cell Mol Med. 2019 Oct;23(10):6744-6754. doi: 10.1111/jcmm.14552. Epub 2019 Aug 11.
• [4] Expression of high molecular weight cysteine proteinase inhibitor in ovarian cancer tissues: regulation of cathepsin B expression by placental CPI.Biol Chem. 2003 Jul;384(7):1103-7. doi: 10.1515/BC.2003.123.
• [5] 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.
• [6] 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.
• [7] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [8] 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.
• [9] Proteasome inhibition creates a chromatin landscape favorable to RNA Pol II processivity. J Biol Chem. 2020 Jan 31;295(5):1271-1287. doi: 10.1074/jbc.RA119.011174. Epub 2019 Dec 5.
• [10] Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicol Sci. 2011 Mar;120(1):33-41. doi: 10.1093/toxsci/kfq375. Epub 2010 Dec 22.