Details of Drug Off-Target (DOT)

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

• DOT Name: Cystatin-M (CST6)
• Synonyms: Cystatin-6; Cystatin-E
• Gene Name: CST6
• Related Disease:
  Advanced cancer
  Brain neoplasm
  Hepatocellular carcinoma
  Atopic dermatitis
  Breast cancer
  Breast carcinoma
  Carcinoma
  Dilated cardiomyopathy 1A
  Ectodermal dysplasia 15, hypohidrotic/hair type
  Gastric cancer
  Glioma
  Head-neck squamous cell carcinoma
  Hypotrichosis
  Hypotrichosis 7
  Inflammatory breast cancer
  Invasive ductal breast carcinoma
  Lung adenocarcinoma
  Melanoma
  Neoplasm
  Oropharyngeal squamous cell carcinoma
  Ovarian cancer
  Pancreatic tumour
  Precancerous condition
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Psoriasis
  Skin disease
  Stomach cancer
  Alopecia
  Ductal breast carcinoma in situ
  Invasive breast carcinoma
  Autosomal recessive congenital ichthyosis 4B
  Metastatic malignant neoplasm
  Non-small-cell lung cancer
  Thyroid tumor
• UniProt ID: CYTM_HUMAN
• PDB ID: 4N6L; 4N6M; 4N6N; 4N6O; 6FK0
• Pfam ID: PF00031
• Sequence:
  MARSNLPLALGLALVAFCLLALPRDARARPQERMVGELRDLSPDDPQVQKAAQAAVASYN
  MGSNSIYYFRDTHIIKAQSQLVAGIKYFLTMEMGSTDCRKTRVTGDHVDLTTCPLAAGAQ
  QEKLRCDFEVLVVPWQNSSQLLKHNCVQM
• Function: High affinity inhibitor for cathepsin L, cathepsin L2 (cathepsin V), and legumain. Involved in the regulation of epidermal cornification, and hair follicle morphogenesis and maintenance.
• Tissue Specificity: Restricted to the stratum granulosum of normal skin, the stratum granulosum/spinosum of psoriatic skin, and the secretory coils of eccrine sweat glands. Low expression levels are found in the nasal cavity.

Molecular Interaction Atlas (MIA) of This DOT

36 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Posttranslational Modification	[1]
Brain neoplasm	DISY3EKS	Definitive	Posttranslational Modification	[2]
Hepatocellular carcinoma	DIS0J828	Definitive	Altered Expression	[3]
Atopic dermatitis	DISTCP41	Strong	Altered Expression	[4]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[5]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Altered Expression	[7]
Ectodermal dysplasia 15, hypohidrotic/hair type	DISMD8J7	Strong	Autosomal recessive	[8]
Gastric cancer	DISXGOUK	Strong	Biomarker	[6]
Glioma	DIS5RPEH	Strong	Altered Expression	[2]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[9]
Hypotrichosis	DISSW933	Strong	Genetic Variation	[8]
Hypotrichosis 7	DISDFBQ5	Strong	Biomarker	[8]
Inflammatory breast cancer	DIS3QRWA	Strong	Posttranslational Modification	[10]
Invasive ductal breast carcinoma	DIS43J58	Strong	Altered Expression	[7]
Lung adenocarcinoma	DISD51WR	Strong	Biomarker	[11]
Melanoma	DIS1RRCY	Strong	Biomarker	[12]
Neoplasm	DISZKGEW	Strong	Biomarker	[13]
Oropharyngeal squamous cell carcinoma	DIS7D7QV	Strong	Altered Expression	[14]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[15]
Pancreatic tumour	DIS3U0LK	Strong	Altered Expression	[16]
Precancerous condition	DISV06FL	Strong	Altered Expression	[17]
Prostate cancer	DISF190Y	Strong	Posttranslational Modification	[18]
Prostate carcinoma	DISMJPLE	Strong	Posttranslational Modification	[18]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[18]
Psoriasis	DIS59VMN	Strong	Altered Expression	[4]
Skin disease	DISDW8R6	Strong	Biomarker	[4]
Stomach cancer	DISKIJSX	Strong	Biomarker	[6]
Alopecia	DIS37HU4	moderate	Biomarker	[19]
Ductal breast carcinoma in situ	DISLCJY7	moderate	Biomarker	[10]
Invasive breast carcinoma	DISANYTW	moderate	Biomarker	[10]
Autosomal recessive congenital ichthyosis 4B	DIS687J0	Limited	Biomarker	[20]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[5]
Non-small-cell lung cancer	DIS5Y6R9	Limited	Biomarker	[21]
Thyroid tumor	DISLVKMD	Limited	Biomarker	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cystatin-M (CST6).	[23]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Cystatin-M (CST6).	[24]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Cystatin-M (CST6).	[25]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Cystatin-M (CST6).	[26]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Cystatin-M (CST6).	[27]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Cystatin-M (CST6).	[28]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Cystatin-M (CST6).	[29]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Cystatin-M (CST6).	[30]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the expression of Cystatin-M (CST6).	[31]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Cystatin-M (CST6).	[32]
Seocalcitol	DMKL9QO	Phase 3	Seocalcitol increases the expression of Cystatin-M (CST6).	[26]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Cystatin-M (CST6).	[33]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Cystatin-M (CST6).	[35]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Cystatin-M (CST6).	[18]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Cystatin-M (CST6).	[37]

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 decreases the methylation of Cystatin-M (CST6).	[34]

References

• [1] A closed-tube methylation-sensitive high resolution melting assay (MS-HRMA) for the semi-quantitative determination of CST6 promoter methylation in clinical samples.BMC Cancer. 2012 Oct 22;12:486. doi: 10.1186/1471-2407-12-486.
• [2] Invasion suppressor cystatin E/M (CST6): high-level cell type-specific expression in normal brain and epigenetic silencing in gliomas.Lab Invest. 2008 Sep;88(9):910-25. doi: 10.1038/labinvest.2008.66. Epub 2008 Jul 7.
• [3] Investigation of the clinical significance and prospective molecular mechanisms of cystatin genes in patients with hepatitis B virusrelated hepatocellular carcinoma.Oncol Rep. 2019 Jul;42(1):189-201. doi: 10.3892/or.2019.7154. Epub 2019 May 9.
• [4] The cystatin M/E-controlled pathway of skin barrier formation: expression of its key components in psoriasis and atopic dermatitis.Br J Dermatol. 2009 Aug;161(2):253-64. doi: 10.1111/j.1365-2133.2009.09156.x. Epub 2009 Apr 24.
• [5] TBX2 represses CST6 resulting in uncontrolled legumain activity to sustain breast cancer proliferation: a novel cancer-selective target pathway with therapeutic opportunities.Oncotarget. 2014 Mar 30;5(6):1609-20. doi: 10.18632/oncotarget.1707.
• [6] Cystatin M expression is reduced in gastric carcinoma and is associated with promoter hypermethylation.Biochem Biophys Res Commun. 2010 Jan 1;391(1):1070-4. doi: 10.1016/j.bbrc.2009.12.022. Epub 2009 Dec 10.
• [7] Cystatin m: a novel candidate tumor suppressor gene for breast cancer.Cancer Res. 2004 Oct 1;64(19):6957-64. doi: 10.1158/0008-5472.CAN-04-0819.
• [8] Deficiency of the human cysteine protease inhibitor cystatin M/E causes hypotrichosis and dry skin. Genet Med. 2019 Jul;21(7):1559-1567. doi: 10.1038/s41436-018-0355-3. Epub 2018 Nov 14.
• [9] 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.
• [10] Cystatin M loss is associated with the losses of estrogen receptor, progesterone receptor, and HER4 in invasive breast cancer.Breast Cancer Res. 2010;12(6):R100. doi: 10.1186/bcr2783. Epub 2010 Nov 23.
• [11] Genome-wide unmasking of epigenetically silenced genes in lung adenocarcinoma from smokers and never smokers.Carcinogenesis. 2014 Jun;35(6):1248-57. doi: 10.1093/carcin/bgt494. Epub 2014 Jan 7.
• [12] Low-level internalization of cystatin E/M affects legumain activity and migration of melanoma cells.J Biol Chem. 2017 Sep 1;292(35):14413-14424. doi: 10.1074/jbc.M117.776138. Epub 2017 Jun 19.
• [13] Cystatin E/M Suppresses Tumor Cell Growth through Cytoplasmic Retention of NF-B.Mol Cell Biol. 2016 May 31;36(12):1776-92. doi: 10.1128/MCB.00878-15. Print 2016 Jun 15.
• [14] Upregulation of cystatin M during the progression of oropharyngeal squamous cell carcinoma from primary tumor to metastasis.Oral Oncol. 2003 Sep;39(6):559-68. doi: 10.1016/s1368-8375(03)00038-1.
• [15] 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.
• [16] Over-expression of cysteine proteinase inhibitor cystatin 6 promotes pancreatic cancer growth.Cancer Sci. 2008 Aug;99(8):1626-32. doi: 10.1111/j.1349-7006.2008.00869.x.
• [17] DNA methylation-dependent silencing of CST6 in human breast cancer cell lines.Lab Invest. 2006 Dec;86(12):1233-42. doi: 10.1038/labinvest.3700485. Epub 2006 Oct 16.
• [18] Frequent loss of cystatin E/M expression implicated in the progression of prostate cancer. Oncogene. 2009 Aug 6;28(31):2829-38. doi: 10.1038/onc.2009.134. Epub 2009 Jun 8.
• [19] Cathepsin B as a potential cystatin M/E target in the mouse hair follicle.FASEB J. 2017 Oct;31(10):4286-4294. doi: 10.1096/fj.201700267R. Epub 2017 Jun 8.
• [20] Evidence that unrestricted legumain activity is involved in disturbed epidermal cornification in cystatin M/E deficient mice.Hum Mol Genet. 2004 May 15;13(10):1069-79. doi: 10.1093/hmg/ddh115. Epub 2004 Mar 25.
• [21] Pharmacologic inhibition of epigenetic modifications, coupled with gene expression profiling, reveals novel targets of aberrant DNA methylation and histone deacetylation in lung cancer.Oncogene. 2007 Apr 19;26(18):2621-34. doi: 10.1038/sj.onc.1210041. Epub 2006 Oct 9.
• [22] Gene expression profiling of papillary thyroid carcinoma identifies transcripts correlated with BRAF mutational status and lymph node metastasis.Clin Cancer Res. 2008 Aug 1;14(15):4735-42. doi: 10.1158/1078-0432.CCR-07-4372.
• [23] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [24] Effect of retinoic acid on gene expression in human conjunctival epithelium: secretory phospholipase A2 mediates retinoic acid induction of MUC16. Invest Ophthalmol Vis Sci. 2005 Nov;46(11):4050-61.
• [25] Research resource: STR DNA profile and gene expression comparisons of human BG-1 cells and a BG-1/MCF-7 clonal variant. Mol Endocrinol. 2014 Dec;28(12):2072-81.
• [26] Expression profiling in squamous carcinoma cells reveals pleiotropic effects of vitamin D3 analog EB1089 signaling on cell proliferation, differentiation, and immune system regulation. Mol Endocrinol. 2002 Jun;16(6):1243-56.
• [27] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [28] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [29] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [30] Characterization of DOK1, a candidate tumor suppressor gene, in epithelial ovarian cancer. Mol Oncol. 2011 Oct;5(5):438-53. doi: 10.1016/j.molonc.2011.07.003. Epub 2011 Jul 26.
• [31] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [32] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [33] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [34] 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.
• [35] Bisphenol A stimulates the epithelial mesenchymal transition of estrogen negative breast cancer cells via FOXA1 signals. Arch Biochem Biophys. 2015 Nov 1;585:10-16. doi: 10.1016/j.abb.2015.09.006. Epub 2015 Sep 9.
• [36] Frequent loss of cystatin E/M expression implicated in the progression of prostate cancer. Oncogene. 2009 Aug 6;28(31):2829-38. doi: 10.1038/onc.2009.134. Epub 2009 Jun 8.
• [37] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.