Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5M4OT4)

• DOT Name: NAD-dependent protein deacetylase sirtuin-7 (SIRT7)
• Synonyms: EC 2.3.1.286; NAD-dependent protein deacylase sirtuin-7; EC 2.3.1.-; Regulatory protein SIR2 homolog 7; SIR2-like protein 7
• Gene Name: SIRT7
• Related Disease:
  Advanced cancer
  Angiosarcoma
  Arteriosclerosis
  Atherosclerosis
  Bladder cancer
  Bone osteosarcoma
  Breast neoplasm
  Carcinoma of liver and intrahepatic biliary tract
  Cardiovascular disease
  Cervical cancer
  Cervical carcinoma
  Cholangiocarcinoma
  Colorectal carcinoma
  Congenital contractural arachnodactyly
  Diabetic kidney disease
  Fatty liver disease
  Glioma
  Head-neck squamous cell carcinoma
  Hepatitis B virus infection
  Liver cancer
  Neoplasm
  Non-small-cell lung cancer
  Obesity
  Osteosarcoma
  Prostate cancer
  Prostate carcinoma
  Pulmonary fibrosis
  Squamous cell carcinoma
  Systemic sclerosis
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid gland papillary carcinoma
  Thyroid tumor
  Urinary bladder cancer
  Urinary bladder neoplasm
  Breast cancer
  Breast carcinoma
  Carcinoma
  Myocardial ischemia
  Osteoarthritis
  Endometrial cancer
  Endometrial carcinoma
  Asthma
  Leukemia
  Lymphoma
  Metastatic malignant neoplasm
  Rectal carcinoma
  Type-1/2 diabetes
• UniProt ID: SIR7_HUMAN
• PDB ID: 5IQZ; 6G0S
• EC Number: 2.3.1.-; 2.3.1.286
• Pfam ID: PF02146
• Sequence:
  MAAGGLSRSERKAAERVRRLREEQQRERLRQVSRILRKAAAERSAEEGRLLAESADLVTE
  LQGRSRRREGLKRRQEEVCDDPEELRGKVRELASAVRNAKYLVVYTGAGISTAASIPDYR
  GPNGVWTLLQKGRSVSAADLSEAEPTLTHMSITRLHEQKLVQHVVSQNCDGLHLRSGLPR
  TAISELHGNMYIEVCTSCVPNREYVRVFDVTERTALHRHQTGRTCHKCGTQLRDTIVHFG
  ERGTLGQPLNWEAATEAASRADTILCLGSSLKVLKKYPRLWCMTKPPSRRPKLYIVNLQW
  TPKDDWAALKLHGKCDDVMRLLMAELGLEIPAYSRWQDPIFSLATPLRAGEEGSHSRKSL
  CRSREEAPPGDRGAPLSSAPILGGWFGRGCTKRTKRKKVT
• Function: NAD-dependent protein-lysine deacylase that can act both as a deacetylase or deacylase (desuccinylase, depropionylase, deglutarylase and dedecanoylase), depending on the context. Specifically mediates deacetylation of histone H3 at 'Lys-18' (H3K18Ac). In contrast to other histone deacetylases, displays strong preference for a specific histone mark, H3K18Ac, directly linked to control of gene expression. H3K18Ac is mainly present around the transcription start site of genes and has been linked to activation of nuclear hormone receptors; SIRT7 thereby acts as a transcription repressor. Moreover, H3K18 hypoacetylation has been reported as a marker of malignancy in various cancers and seems to maintain the transformed phenotype of cancer cells. Also able to mediate deacetylation of histone H3 at 'Lys-36' (H3K36Ac) in the context of nucleosomes. Also mediates deacetylation of non-histone proteins, such as ATM, CDK9, DDX21, DDB1, FBL, FKBP5/FKBP51, GABPB1, RAN, RRP9/U3-55K and POLR1E/PAF53. Enriched in nucleolus where it stimulates transcription activity of the RNA polymerase I complex. Acts by mediating the deacetylation of the RNA polymerase I subunit POLR1E/PAF53, thereby promoting the association of RNA polymerase I with the rDNA promoter region and coding region. In response to metabolic stress, SIRT7 is released from nucleoli leading to hyperacetylation of POLR1E/PAF53 and decreased RNA polymerase I transcription. Required to restore the transcription of ribosomal RNA (rRNA) at the exit from mitosis. Promotes pre-ribosomal RNA (pre-rRNA) cleavage at the 5'-terminal processing site by mediating deacetylation of RRP9/U3-55K, a core subunit of the U3 snoRNP complex. Mediates 'Lys-37' deacetylation of Ran, thereby regulating the nuclear export of NF-kappa-B subunit RELA/p65. Acts as a regulator of DNA damage repair by mediating deacetylation of ATM during the late stages of DNA damage response, promoting ATM dephosphorylation and deactivation. Suppresses the activity of the DCX (DDB1-CUL4-X-box) E3 ubiquitin-protein ligase complexes by mediating deacetylation of DDB1, which prevents the interaction between DDB1 and CUL4 (CUL4A or CUL4B). Activates RNA polymerase II transcription by mediating deacetylation of CDK9, thereby promoting 'Ser-2' phosphorylation of the C-terminal domain (CTD) of RNA polymerase II. Deacetylates FBL, promoting histone-glutamine methyltransferase activity of FBL. Acts as a regulator of mitochondrial function by catalyzing deacetylation of GABPB1. Regulates Akt/AKT1 activity by mediating deacetylation of FKBP5/FKBP51. Required to prevent R-loop-associated DNA damage and transcription-associated genomic instability by mediating deacetylation and subsequent activation of DDX21, thereby overcoming R-loop-mediated stalling of RNA polymerases. In addition to protein deacetylase activity, also acts as a protein-lysine deacylase. Acts as a protein depropionylase by mediating depropionylation of Osterix (SP7), thereby regulating bone formation by osteoblasts. Acts as a histone deglutarylase by mediating deglutarylation of histone H4 on 'Lys-91' (H4K91glu); a mark that destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes. Acts as a histone desuccinylase: in response to DNA damage, recruited to DNA double-strand breaks (DSBs) and catalyzes desuccinylation of histone H3 on 'Lys-122' (H3K122succ), thereby promoting chromatin condensation and DSB repair. Also promotes DSB repair by promoting H3K18Ac deacetylation, regulating non-homologous end joining (NHEJ). Along with its role in DNA repair, required for chromosome synapsis during prophase I of female meiosis by catalyzing H3K18Ac deacetylation. Involved in transcriptional repression of LINE-1 retrotransposon via H3K18Ac deacetylation, and promotes their association with the nuclear lamina. Required to stabilize ribosomal DNA (rDNA) heterochromatin and prevent cellular senescence induced by rDNA instability. Acts as a negative regulator of SIRT1 by preventing autodeacetylation of SIRT1, restricting SIRT1 deacetylase activity.
• KEGG Pathway:
  Nicoti.te and nicoti.mide metabolism (hsa00760)
  Metabolic pathways (hsa01100)

Molecular Interaction Atlas (MIA) of This DOT

48 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Angiosarcoma	DISIYS9W	Strong	Altered Expression	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Bladder cancer	DISUHNM0	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[6]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[7]
Cardiovascular disease	DIS2IQDX	Strong	Biomarker	[1]
Cervical cancer	DISFSHPF	Strong	Biomarker	[8]
Cervical carcinoma	DIST4S00	Strong	Biomarker	[8]
Cholangiocarcinoma	DIS71F6X	Strong	Biomarker	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[10]
Congenital contractural arachnodactyly	DISOM1K7	Strong	Altered Expression	[9]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[11]
Fatty liver disease	DIS485QZ	Strong	Biomarker	[12]
Glioma	DIS5RPEH	Strong	Biomarker	[13]
Head-neck squamous cell carcinoma	DISF7P24	Strong	Biomarker	[14]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[15]
Liver cancer	DISDE4BI	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Biomarker	[16]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[17]
Obesity	DIS47Y1K	Strong	Biomarker	[18]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Prostate cancer	DISF190Y	Strong	Biomarker	[19]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[19]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[20]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[21]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[22]
Thyroid cancer	DIS3VLDH	Strong	Altered Expression	[23]
Thyroid gland carcinoma	DISMNGZ0	Strong	Altered Expression	[23]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[23]
Thyroid tumor	DISLVKMD	Strong	Altered Expression	[23]
Urinary bladder cancer	DISDV4T7	Strong	Biomarker	[4]
Urinary bladder neoplasm	DIS7HACE	Strong	Biomarker	[4]
Breast cancer	DIS7DPX1	moderate	Biomarker	[24]
Breast carcinoma	DIS2UE88	moderate	Biomarker	[24]
Carcinoma	DISH9F1N	moderate	Biomarker	[10]
Myocardial ischemia	DISFTVXF	moderate	Biomarker	[25]
Osteoarthritis	DIS05URM	moderate	Biomarker	[26]
Endometrial cancer	DISW0LMR	Disputed	Biomarker	[27]
Endometrial carcinoma	DISXR5CY	Disputed	Biomarker	[27]
Asthma	DISW9QNS	Limited	Biomarker	[28]
Leukemia	DISNAKFL	Limited	Genetic Variation	[29]
Lymphoma	DISN6V4S	Limited	Genetic Variation	[29]
Metastatic malignant neoplasm	DIS86UK6	Limited	Altered Expression	[30]
Rectal carcinoma	DIS8FRR7	Limited	Altered Expression	[31]
Type-1/2 diabetes	DISIUHAP	Limited	Biomarker	[32]

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 NAD-dependent protein deacetylase sirtuin-7 (SIRT7).	[33]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of NAD-dependent protein deacetylase sirtuin-7 (SIRT7).	[40]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of NAD-dependent protein deacetylase sirtuin-7 (SIRT7).	[34]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of NAD-dependent protein deacetylase sirtuin-7 (SIRT7).	[35]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of NAD-dependent protein deacetylase sirtuin-7 (SIRT7).	[36]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of NAD-dependent protein deacetylase sirtuin-7 (SIRT7).	[37]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of NAD-dependent protein deacetylase sirtuin-7 (SIRT7).	[38]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of NAD-dependent protein deacetylase sirtuin-7 (SIRT7).	[39]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of NAD-dependent protein deacetylase sirtuin-7 (SIRT7).	[41]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of NAD-dependent protein deacetylase sirtuin-7 (SIRT7).	[42]
NORCANTHARIDIN	DM9B6Y1	Investigative	NORCANTHARIDIN decreases the expression of NAD-dependent protein deacetylase sirtuin-7 (SIRT7).	[38]

References

• [1] Role of N-terminus in function and dynamics of sirtuin 7: an in silico study.J Biomol Struct Dyn. 2020 Mar;38(5):1283-1291. doi: 10.1080/07391102.2019.1600585. Epub 2019 Apr 26.
• [2] MicroRNA-340 inhibits the growth and invasion of angiosarcoma cells by targeting SIRT7.Biomed Pharmacother. 2018 Jul;103:1061-1068. doi: 10.1016/j.biopha.2018.04.148. Epub 2018 Apr 25.
• [3] SIRT7 Regulates the Vascular Smooth Muscle Cells Proliferation and Migration via Wnt/-Catenin Signaling Pathway.Biomed Res Int. 2018 Dec 4;2018:4769596. doi: 10.1155/2018/4769596. eCollection 2018.
• [4] Hsa-miR-125b suppresses bladder cancer development by down-regulating oncogene SIRT7 and oncogenic long non-coding RNA MALAT1.FEBS Lett. 2013 Nov 29;587(23):3875-82.
• [5] Sirtuin 7 plays an oncogenic role in human osteosarcoma via downregulating CDC4 expression.Am J Cancer Res. 2017 Sep 1;7(9):1788-1803. eCollection 2017.
• [6] Altered sirtuin expression is associated with node-positive breast cancer.Br J Cancer. 2006 Oct 23;95(8):1056-61. doi: 10.1038/sj.bjc.6603384. Epub 2006 Sep 26.
• [7] SIRT7 regulates hepatocellular carcinoma response to therapy by altering the p53-dependent cell death pathway.J Exp Clin Cancer Res. 2019 Jun 13;38(1):252. doi: 10.1186/s13046-019-1246-4.
• [8] Expression/localization patterns of sirtuins (SIRT1, SIRT2, and SIRT7) during progression of cervical cancer and effects of sirtuin inhibitors on growth of cervical cancer cells.Tumour Biol. 2015 Aug;36(8):6159-71. doi: 10.1007/s13277-015-3300-y. Epub 2015 Mar 21.
• [9] Sirtuin7 has an oncogenic potential via promoting the growth of cholangiocarcinoma cells.Biomed Pharmacother. 2018 Apr;100:257-266. doi: 10.1016/j.biopha.2018.02.007. Epub 2018 Feb 16.
• [10] Sirtuin 7 promotes colorectal carcinoma proliferation and invasion through the inhibition of E-cadherin.Exp Ther Med. 2018 Mar;15(3):2333-2342. doi: 10.3892/etm.2017.5673. Epub 2017 Dec 22.
• [11] microRNA-20b contributes to high glucose-induced podocyte apoptosis by targeting SIRT7.Mol Med Rep. 2017 Oct;16(4):5667-5674. doi: 10.3892/mmr.2017.7224. Epub 2017 Aug 10.
• [12] Sirtuin 7-dependent deacetylation of DDB1 regulates the expression of nuclear receptor TR4.Biochem Biophys Res Commun. 2017 Aug 19;490(2):423-428. doi: 10.1016/j.bbrc.2017.06.057. Epub 2017 Jun 14.
• [13] Sirtuin 7 promotes glioma proliferation and invasion through activation of the ERK/STAT3 signaling pathway.Oncol Lett. 2019 Feb;17(2):1445-1452. doi: 10.3892/ol.2018.9800. Epub 2018 Dec 6.
• [14] The potential of SIRT6 and SIRT7 as circulating markers for head and neck squamous cell carcinoma.Anticancer Res. 2014 Dec;34(12):7137-43.
• [15] Stabilization of SIRT7 deacetylase by viral oncoprotein HBx leads to inhibition of growth restrictive RPS7 gene and facilitates cellular transformation.Sci Rep. 2015 Oct 7;5:14806. doi: 10.1038/srep14806.
• [16] Disruption of SIRT7 Increases the Efficacy of Checkpoint Inhibitor via MEF2D Regulation of Programmed Cell Death 1 Ligand 1 in Hepatocellular Carcinoma Cells.Gastroenterology. 2020 Feb;158(3):664-678.e24. doi: 10.1053/j.gastro.2019.10.025. Epub 2019 Oct 31.
• [17] MicroRNA-3666-induced suppression of SIRT7 inhibits the growth of non-small cell lung cancer cells.Oncol Rep. 2016 Nov;36(5):3051-3057. doi: 10.3892/or.2016.5063. Epub 2016 Sep 5.
• [18] SIRT7 functions in redox homeostasis and cytoskeletal organization during oocyte maturation.FASEB J. 2018 Jun 7:fj201800078RR. doi: 10.1096/fj.201800078RR. Online ahead of print.
• [19] Sirtuin 7: a new marker of aggressiveness in prostate cancer.Oncotarget. 2017 Aug 24;8(44):77309-77316. doi: 10.18632/oncotarget.20468. eCollection 2017 Sep 29.
• [20] Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts.Am J Physiol Lung Cell Mol Physiol. 2017 Jun 1;312(6):L945-L958. doi: 10.1152/ajplung.00473.2016. Epub 2017 Apr 6.
• [21] Associations of sirtuins with clinicopathological parameters and prognosis in non-small cell lung cancer.Cancer Manag Res. 2018 Sep 10;10:3341-3356. doi: 10.2147/CMAR.S166946. eCollection 2018.
• [22] The Histone Deacetylase Sirtuin 1 Is Reduced in Systemic Sclerosis and Abrogates Fibrotic Responses by Targeting Transforming Growth Factor Signaling. Arthritis Rheumatol. 2015 May;67(5):1323-34. doi: 10.1002/art.39061.
• [23] SIRT7 promotes thyroid tumorigenesis through phosphorylation and activation of Akt and p70S6K1 via DBC1/SIRT1 axis.Oncogene. 2019 Jan;38(3):345-359. doi: 10.1038/s41388-018-0434-6. Epub 2018 Aug 9.
• [24] SIRT7 depletion inhibits cell proliferation, migration, and increases drug sensitivity by activating p38MAPK in breast cancer cells.J Cell Physiol. 2018 Sep;233(9):6767-6778. doi: 10.1002/jcp.26398. Epub 2018 Mar 25.
• [25] Suppression of microRNA-142-5p attenuates hypoxia-induced apoptosis through targeting SIRT7.Biomed Pharmacother. 2017 Oct;94:394-401. doi: 10.1016/j.biopha.2017.07.083. Epub 2017 Aug 1.
• [26] SIRT7 is an important regulator of cartilage homeostasis and osteoarthritis development.Biochem Biophys Res Commun. 2018 Feb 2:S0006-291X(18)30144-X. doi: 10.1016/j.bbrc.2018.01.129. Online ahead of print.
• [27] Sirtuin-7 knockdown inhibits the growth of endometrial cancer cells by inducing apoptosis via the NF-B signaling pathway.Oncol Lett. 2019 Jan;17(1):937-943. doi: 10.3892/ol.2018.9698. Epub 2018 Nov 14.
• [28] SIRT7 regulates the TGF-1-induced proliferation and migration of mouse airway smooth muscle cells by modulating the expression of TGF- receptor I.Biomed Pharmacother. 2018 Aug;104:781-787. doi: 10.1016/j.biopha.2018.05.060. Epub 2018 May 29.
• [29] Fluorescence in situ hybridization and chromosomal organization of the human Sirtuin 7 gene.Int J Oncol. 2006 Apr;28(4):899-908.
• [30] Development and validation of SIRT3-related nomogram predictive of overall survival in patients with serous ovarian cancer.J Ovarian Res. 2019 May 21;12(1):47. doi: 10.1186/s13048-019-0524-2.
• [31] Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer.Theranostics. 2017 Mar 22;7(5):1346-1359. doi: 10.7150/thno.18804. eCollection 2017.
• [32] Distinctive Roles of Sirtuins on Diabetes, Protective or Detrimental?.Front Endocrinol (Lausanne). 2018 Nov 29;9:724. doi: 10.3389/fendo.2018.00724. eCollection 2018.
• [33] 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.
• [34] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [35] Increased mitochondrial ROS formation by acetaminophen in human hepatic cells is associated with gene expression changes suggesting disruption of the mitochondrial electron transport chain. Toxicol Lett. 2015 Apr 16;234(2):139-50.
• [36] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [37] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [38] Norcantharidin combined with paclitaxel induces endoplasmic reticulum stress mediated apoptotic effect in prostate cancer cells by targeting SIRT7 expression. Environ Toxicol. 2021 Nov;36(11):2206-2216. doi: 10.1002/tox.23334. Epub 2021 Jul 16.
• [39] Curcumin induces oxidation-dependent cell cycle arrest mediated by SIRT7 inhibition of rDNA transcription in human aortic smooth muscle cells. Toxicol Lett. 2015 Mar 18;233(3):227-38. doi: 10.1016/j.toxlet.2015.01.019. Epub 2015 Jan 30.
• [40] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [41] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [42] Genome-Wide Analysis of Low Dose Bisphenol-A (BPA) Exposure in Human Prostate Cells. Curr Genomics. 2019 May;20(4):260-274. doi: 10.2174/1389202920666190603123040.