Molecule Information

General Information of the Molecule (ID: Mol01968)

• Name: Sirtuin 6 (SIRT6) ,Homo sapiens
• Synonyms: SIRT6; SIR2L6
• Molecule Type: Protein
• Gene Name: SIRT6
• Gene ID: 51548
• Location: chr19:4,174,109-4,182,566[-]
• Sequence:
  MSVNYAAGLSPYADKGKCGLPEIFDPPEELERKVWELARLVWQSSSVVFHTGAGISTASG
  IPDFRGPHGVWTMEERGLAPKFDTTFESARPTQTHMALVQLERVGLLRFLVSQNVDGLHV
  RSGFPRDKLAELHGNMFVEECAKCKTQYVRDTVVGTMGLKATGRLCTVAKARGLRACRGE
  LRDTILDWEDSLPDRDLALADEASRNADLSITLGTSLQIRPSGNLPLATKRRGGRLVIVN
  LQPTKHDRHADLRIHGYVDEVMTRLMKHLGLEIPAWDGPRVLERALPPLPRPPTPKLEPK
  EESPTRINGSIPAGPKQEPCAQHNGSEPASPKRERPTSPAPHRPPKRVKAKAVPS
• Function: NAD-dependent protein deacetylase, deacylase and mono-ADP-ribosyltransferase that plays an essential role in DNA damage repair, telomere maintenance, metabolic homeostasis, inflammation, tumorigenesis and aging. Displays protein-lysine deacetylase or defatty-acylase (demyristoylase and depalmitoylase) activity, depending on the context. Acts as a key histone deacetylase by catalyzing deacetylation of histone H3 at 'Lys-9', 'Lys-18' and 'Lys-56' (H3K9ac, H3K18ac and H3K56ac, respectively), suppressing target gene expression of several transcription factors, including NF-kappa-B. Acts as an inhibitor of transcription elongation by mediating deacetylation of H3K9ac and H3K56ac, preventing release of NELFE from chromatin and causing transcriptional pausing. Involved in DNA repair by promoting double-strand break (DSB) repair: acts as a DSB sensor by recognizing and binding DSB sites, leading to recruitment of DNA repair proteins, such as SMARCA5/SNF2H, and deacetylation of histone H3K9ac and H3K56ac. SIRT6 participation to DSB repair is probably involved in extension of life span. Also promotes DNA repair by deacetylating non-histone proteins, such as DDB2 and p53/TP53. Specifically deacetylates H3K18ac at pericentric heterochromatin, thereby maintaining pericentric heterochromatin silencing at centromeres and protecting against genomic instability and cellular senescence. Involved in telomere maintenance by catalyzing deacetylation of histone H3 in telomeric chromatin, regulating telomere position effect and telomere movement in response to DNA damage. Required for embryonic stem cell differentiation by mediating histone deacetylation of H3K9ac. Plays a major role in metabolism by regulating processes such as glycolysis, gluconeogenesis, insulin secretion and lipid metabolism. Inhibits glycolysis via histone deacetylase activity and by acting as a corepressor of the transcription factor HIF1A, thereby controlling the expression of multiple glycolytic genes. Has tumor suppressor activity by repressing glycolysis, thereby inhibiting the Warburg effect. Also regulates glycolysis and tumorigenesis by mediating deacetylation and nuclear export of non-histone proteins, such as isoform M2 of PKM (PKM2). Acts as a negative regulator of gluconeogenesis by mediating deacetylation of non-histone proteins, such as FOXO1 and KAT2A/GCN5. Promotes beta-oxidation of fatty acids during fasting by catalyzing deacetylation of NCOA2, inducing coactivation of PPARA. Acts as a regulator of lipid catabolism in brown adipocytes, both by catalyzing deacetylation of histones and non-histone proteins, such as FOXO1. Also acts as a regulator of circadian rhythms, both by regulating expression of clock-controlled genes involved in lipid and carbohydrate metabolism, and by catalyzing deacetylation of PER2. The defatty-acylase activity is specifically involved in regulation of protein secretion. Has high activity toward long-chain fatty acyl groups and mediates protein-lysine demyristoylation and depalmitoylation of target proteins, such as RRAS2 and TNF, thereby regulating their secretion. Also acts as a mono-ADP-ribosyltransferase by mediating mono-ADP-ribosylation of PARP1, TRIM28/KAP1 or SMARCC2/BAF170. Mono-ADP-ribosyltransferase activity is involved in DNA repair, cellular senescence, repression of LINE-1 retrotransposon elements and regulation of transcription.
• Uniprot ID: SIR6_HUMAN
• Ensembl ID: ENSG00000077463
• HGNC ID: HGNC:14934

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 1 drug(s) in total

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Diffuse large B-cell lymphoma [1]

• Resistant Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MET/PI3K/AKT/mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: Val cells; Bone marrow; Homo sapiens (Human); CVCL_1819
• In Vitro Model: LY1 cells; Ovary; Homo sapiens (Human); CVCL_ZU83
• In Vitro Model: DLBCL cells; Lymph node; Homo sapiens (Human); N.A.
• In Vitro Model: LY8 cells; Lymph node; Homo sapiens (Human); CVCL_8803
• In Vitro Model: LY3 cells; Bone marrow; Homo sapiens (Human); CVCL_8800
• In Vivo Model: Beige mice xenografts model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: Sirt6 expression was raised in DLBCL, with its high levels corresponding to poor patient outcomes. Sirt6 was also found to promote tumorigenesis by regulating the PI3K/Akt/mTOR pathway. Targeting Sirt6 exerted anti-lymphoma activity and enhanced chemo-sensitivity. OSS_128167 may prove to be a useful component in further development of novel chemotherapy regimens in DLBCL.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Diffuse large B-cell lymphoma [1]

• Sensitive Disease: Diffuse large B-cell lymphoma [ICD-11: 2A81.0]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MET/PI3K/AKT/mTOR signaling pathway; Activation; hsa04150
• In Vitro Model: Val cells; Bone marrow; Homo sapiens (Human); CVCL_1819
• In Vitro Model: LY1 cells; Ovary; Homo sapiens (Human); CVCL_ZU83
• In Vitro Model: DLBCL cells; Lymph node; Homo sapiens (Human); N.A.
• In Vitro Model: LY8 cells; Lymph node; Homo sapiens (Human); CVCL_8803
• In Vitro Model: LY3 cells; Bone marrow; Homo sapiens (Human); CVCL_8800
• In Vivo Model: Beige mice xenografts model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: Sirt6 expression was raised in DLBCL, with its high levels corresponding to poor patient outcomes. Sirt6 was also found to promote tumorigenesis by regulating the PI3K/Akt/mTOR pathway. Targeting Sirt6 exerted anti-lymphoma activity and enhanced chemo-sensitivity. OSS_128167 may prove to be a useful component in further development of novel chemotherapy regimens in DLBCL.

References

• Ref 1: Sirt6 promotes tumorigenesis and drug resistance of diffuse large B-cell lymphoma by mediating PI3K/Akt signaling .J Exp Clin Cancer Res. 2020 Jul 25;39(1):142. doi: 10.1186/s13046-020-01623-w. 10.1186/s13046-020-01623-w