SIRT1在血液系统肿瘤中的研究进展（英文）
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摘要
SIRT1属于烟酰胺腺嘌呤二核苷酸(NAD)依赖的组蛋白脱乙酰酶家族成员。通过对不同蛋白底物去乙酰化,SIRT1参与了细胞代谢、细胞周期以及DNA修复等多种生理过程的调控。许多研究表明:SIRT1在肿瘤中的功能具有两面性,在急性髓系白血病和慢性粒细胞白血病中SIRT1的高表达促进了疾病的进展;而在骨髓增生异常综合征中,SIRT1的活化却能抑制肿瘤干细胞。本综述回顾了SIRT1在血液系统肿瘤中的研究进展,总结了不同肿瘤类型中SIRT1的表达水平以及相应的调控机制,并探讨了潜在的治疗靶点和应用前景。
Sirtuin 1(SIRT1) is a protein deacetylase, which regulates various physiological activities by deacetylating different protein substrates. An increasing number of studies have revealed critical roles of SIRT1 in different aspects of cancers including metabolism, proliferation, genomic instability, and chemotherapy resistance. Depending on the protein targets in a certain oncogenic context, SIRT1 may play a unique role in each individual blood cancer subtype.Our previous work showed that activation of SIRT1 in primitive leukemia cells of acute myeloid leukemia(AML) and chronic myelogenous leukemia(CML) promotes disease maintenance. On the other hand, an SIRT1 agonist was shown to disrupt maintenance of myelodysplastic syndrome(MDS) stem cells and holds promise as a potential therapeutic approach. Herein, we present a concise summary of the different functions of SIRT1 in hematologic malignancies.
Sirtuin 1(SIRT1) is a protein deacetylase, which regulates various physiological activities by deacetylating different protein substrates. An increasing number of studies have revealed critical roles of SIRT1 in different aspects of cancers including metabolism, proliferation, genomic instability, and chemotherapy resistance. Depending on the protein targets in a certain oncogenic context, SIRT1 may play a unique role in each individual blood cancer subtype.Our previous work showed that activation of SIRT1 in primitive leukemia cells of acute myeloid leukemia(AML) and chronic myelogenous leukemia(CML) promotes disease maintenance. On the other hand, an SIRT1 agonist was shown to disrupt maintenance of myelodysplastic syndrome(MDS) stem cells and holds promise as a potential therapeutic approach. Herein, we present a concise summary of the different functions of SIRT1 in hematologic malignancies.
引文
Audrito V,Vaisitti T,Rossi D,et al.,2011.Nicotinamide blocks proliferation and induces apoptosis of chronic lymphocytic leukemia cells through activation of the p53/miR-34a/SIRT1 tumor suppressor network.Cancer Res,71(13):4473-4483.https://doi.org/10.1158/0008-5472.can-10-4452
Bhalla S,Gordon LI,2016.Functional characterization of NAD dependent deacetylases SIRT1 and SIRT2 in B-cell chronic lymphocytic leukemia(CLL).Cancer Biol Ther,17(3):300-309.https://doi.org/10.1080/15384047.2016.1139246
Bhojwani D,Pui CH,2013.Relapsed childhood acute lymphoblastic leukaemia.Lancet Oncol,14(6):e205-e217.https://doi.org/10.1016/s1470-2045(12)70580-6
Bradbury CA,Khanim FL,Hayden R,et al.,2005.Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors.Leukemia,19(10):1751-1759.https://doi.org/10.1038/sj.leu.2403910
Brooks CL,Gu W,2009.How does SIRT1 affect metabolism,senescence and cancer?Nat Rev Cancer,9(2):123-128.https://doi.org/10.1038/nrc2562
Chalkiadaki A,Guarente L,2015.The multifaceted functions of sirtuins in cancer.Nat Rev Cancer,15(10):608-624.https://doi.org/10.1038/nrc3985
Chen CW,Koche RP,Sinha AU,et al.,2015.DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia.Nat Med,21(4):335-343.https://doi.org/10.1038/nm.3832
Daenthanasanmak A,Iamsawat S,Chakraborty P,et al.,2019.Targeting Sirt-1 controls GVHD by inhibiting T-cell alloresponse and promoting Treg stability in mice.Blood,133(3):266-279.https://doi.org/10.1182/blood-2018-07-863233
dal Bo M,D'Agaro T,Gobessi S,et al.,2015.The SIRT1/TP53axis is activated upon B-cell receptor triggering via miR-132 up-regulation in chronic lymphocytic leukemia cells.Oncotarget,6(22):19102-19117.https://doi.org/10.18632/oncotarget.3905
He ML,Tan B,Vasan K,et al.,2017.SIRT1 and AMPKpathways are essential for the proliferation and survival of primary effusion lymphoma cells.J Pathol,242(3):309-321.https://doi.org/10.1002/path.4905
Heltweg B,Gatbonton T,Schuler AD,et al.,2006.Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes.Cancer Res,66(8):4368-4377.https://doi.org/10.1158/0008-5472.can-05-3617
Herranz D,Serrano M,2010.SIRT1:recent lessons from mouse models.Nat Rev Cancer,10(12):819-823.https://doi.org/10.1038/nrc2962
Huang R,Xu YF,Wan W,et al.,2015.Deacetylation of nuclear LC3 drives autophagy initiation under starvation.Mol Cell,57(3):456-466.https://doi.org/10.1016/j.molcel.2014.12.013
Jang KY,Hwang SH,Kwon KS,et al.,2008.SIRT1 expression is associated with poor prognosis of diffuse large B-cell lymphoma.Am J Surg Pathol,32(10):1523-1531.https://doi.org/10.1097/PAS.0b013e31816b6478
Jin YL,Cao Q,Chen C,et al.,2015.Tenovin-6-mediated inhibition of SIRT1/2 induces apoptosis in acute lymphoblastic leukemia(ALL)cells and eliminates ALLstem/progenitor cells.BMC Cancer,15:226.https://doi.org/10.1186/s12885-015-1282-1
Kan YT,Ge P,Wang XY,et al.,2018.SIRT1 rs3758391polymorphism and risk of diffuse large B cell lymphoma in a Chinese population.Cancer Cell Int,18:163.https://doi.org/10.1186/s12935-018-0659-z
Lee IH,Cao L,Mostoslavsky R,et al.,2008.A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy.Proc Natl Acad Sci USA,105(9):3374-3379.https://doi.org/10.1073/pnas.0712145105
Li L,Wang LS,Li L,et al.,2012.Activation of p53 by SIRT1inhibition enhances elimination of CML leukemia stem cells in combination with imatinib.Cancer Cell,21(2):266-281.https://doi.org/10.1016/j.ccr.2011.12.020
Li L,Osdal T,Ho Y,et al.,2014.SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells.Cell Stem Cell,15(4):431-446.https://doi.org/10.1016/j.stem.2014.08.001
Li L,Ye SG,Yang M,et al.,2015.SIRT1 downregulation enhances chemosensitivity and survival of adult T-cell leukemia-lymphoma cells by reducing DNA doublestrand repair.Oncol Rep,34(6):2935-2942.https://doi.org/10.3892/or.2015.4287
Luo JY,Nikolaev AY,Imai SI,et al.,2001.Negative control of p53 by Sir2αpromotes cell survival under stress.Cell,107(2):137-148.https://doi.org/10.1016/S0092-8674(01)00524-4
Ng SWK,Mitchell A,Kennedy JA,et al.,2016.A 17-gene stemness score for rapid determination of risk in acute leukaemia.Nature,540(7633):433-437.https://doi.org/10.1038/nature20598
Nihal M,Ahmad N,Wood GS,2014.SIRT1 is upregulated in cutaneous T-cell lymphoma,and its inhibition induces growth arrest and apoptosis.Cell Cycle,13(4):632-640.https://doi.org/10.4161/cc.27523
Ou X,Lee MR,Huang XX,et al.,2014.SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress.Stem Cells,32(5):1183-1194.https://doi.org/10.1002/stem.1641
Patel JP,G?nen M,Figueroa ME,et al.,2012.Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.N Engl J Med,366(12):1079-1089.https://doi.org/10.1056/NEJMoa1112304
Pui CH,Relling MV,Downing JR,2004.Mechanisms of disease:acute lymphoblastic leukemia.N Engl J Med,350(15):1535-1548.https://doi.org/10.1056/NEJMra023001
Quesada AE,Assylbekova B,Jabcuga CE,et al.,2015.Expression of Sirt1 and Fox P3 in classical Hodgkin lymphoma and tumor infiltrating lymphocytes:implications for immune dysregulation,prognosis and potential therapeutic targeting.Int J Clin Exp Pathol,8(10):13241-13248.
Rea D,Mahon FX,2018.How I manage relapse of chronic myeloid leukaemia after stopping tyrosine kinase inhibitor therapy.Br J Haematol,180(1):24-32.https://doi.org/10.1111/bjh.14973
Ren RB,2005.Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.Nat Rev Cancer,5(3):172-183.https://doi.org/10.1038/nrc1567
Ross DM,Branford S,Seymour JF,et al.,2013.Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease:results from the TWISTER study.Blood,122(4):515-522.https://doi.org/10.1182/blood-2013-02-483750
Roth M,Wang ZQ,Chen WY,2016.SIRT1 and LSD1 competitively regulate KU70 functions in DNA repair and mutation acquisition in cancer cells.Oncotarget,7(31):50195-50214.https://doi.org/10.18632/oncotarget.10328
Sasca D,H?hnel PS,Szybinski J,et al.,2014.SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia.Blood,124(1):121-133.https://doi.org/10.1182/blood-2013-11-538819
Sperling AS,Gibson CJ,Ebert BL,2017.The genetics of myelodysplastic syndrome:from clonal haematopoiesis to secondary leukaemia.Nat Rev Cancer,17(1):5-19.https://doi.org/10.1038/nrc.2016.112
Sun J,He X,Zhu YH,et al.,2018.SIRT1 activation disrupts maintenance of myelodysplastic syndrome stem and progenitor cells by restoring TET2 function.Cell Stem Cell,23(3):355-369.e9.https://doi.org/10.1016/j.stem.2018.07.018
Tian WL,Guo R,Wang F,et al.,2018.The IRF9-SIRT1-P53axis is involved in the growth of human acute myeloid leukemia.Exp Cell Res,365(2):185-193.https://doi.org/10.1016/j.yexcr.2018.02.036
Vaziri H,Dessain SK,Ng Eaton E,et al.,2001.hSIR2SIRT1functions as an NAD-dependent p53 deacetylase.Cell,107(2):149-159.https://doi.org/10.1016/S0092-8674(01)00527-X
Wang CG,Chen LH,Hou XH,et al.,2006.Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage.Nat Cell Biol,8(9):1025-1031.https://doi.org/10.1038/ncb1468
Wang RH,Sengupta K,Li CL,et al.,2008.Impaired DNAdamage response,genome instability,and tumorigenesis in SIRT1 mutant mice.Cancer Cell,14(4):312-323.https://doi.org/10.1016/j.ccr.2008.09.001
Wang Z,Yuan H,Roth M,et al.,2013.SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells.Oncogene,32(5):589-598.https://doi.org/10.1038/onc.2012.83
Wang ZQ,Chen CC,Chen WY,2015.CD150-side population defines leukemia stem cells in a BALB/c mouse model of CML and is depleted by genetic loss of SIRT1.Stem Cells,33(12):3437-3451.https://doi.org/10.1002/stem.2218
Yuan HF,Wang ZQ,Li L,et al.,2012.Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis.Blood,119(8):1904-1914.https://doi.org/10.1182/blood-2011-06-361691
Yuan HF,He ML,Cheng F,et al.,2017.Tenovin-6 inhibits proliferation and survival of diffuse large B-cell lymphoma cells by blocking autophagy.Oncotarget,8(9):14912-14924.https://doi.org/10.18632/oncotarget.14741
Zhang WJ,Wu HX,Yang M,et al.,2016.SIRT1 inhibition impairs non-homologous end joining DNA damage repair by increasing Ku70 acetylation in chronic myeloid leukemia cells.Oncotarget,7(12):13538-13550.https://doi.org/10.18632/oncotarget.6455
Bhalla S,Gordon LI,2016.Functional characterization of NAD dependent deacetylases SIRT1 and SIRT2 in B-cell chronic lymphocytic leukemia(CLL).Cancer Biol Ther,17(3):300-309.https://doi.org/10.1080/15384047.2016.1139246
Bhojwani D,Pui CH,2013.Relapsed childhood acute lymphoblastic leukaemia.Lancet Oncol,14(6):e205-e217.https://doi.org/10.1016/s1470-2045(12)70580-6
Bradbury CA,Khanim FL,Hayden R,et al.,2005.Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors.Leukemia,19(10):1751-1759.https://doi.org/10.1038/sj.leu.2403910
Brooks CL,Gu W,2009.How does SIRT1 affect metabolism,senescence and cancer?Nat Rev Cancer,9(2):123-128.https://doi.org/10.1038/nrc2562
Chalkiadaki A,Guarente L,2015.The multifaceted functions of sirtuins in cancer.Nat Rev Cancer,15(10):608-624.https://doi.org/10.1038/nrc3985
Chen CW,Koche RP,Sinha AU,et al.,2015.DOT1L inhibits SIRT1-mediated epigenetic silencing to maintain leukemic gene expression in MLL-rearranged leukemia.Nat Med,21(4):335-343.https://doi.org/10.1038/nm.3832
Daenthanasanmak A,Iamsawat S,Chakraborty P,et al.,2019.Targeting Sirt-1 controls GVHD by inhibiting T-cell alloresponse and promoting Treg stability in mice.Blood,133(3):266-279.https://doi.org/10.1182/blood-2018-07-863233
dal Bo M,D'Agaro T,Gobessi S,et al.,2015.The SIRT1/TP53axis is activated upon B-cell receptor triggering via miR-132 up-regulation in chronic lymphocytic leukemia cells.Oncotarget,6(22):19102-19117.https://doi.org/10.18632/oncotarget.3905
He ML,Tan B,Vasan K,et al.,2017.SIRT1 and AMPKpathways are essential for the proliferation and survival of primary effusion lymphoma cells.J Pathol,242(3):309-321.https://doi.org/10.1002/path.4905
Heltweg B,Gatbonton T,Schuler AD,et al.,2006.Antitumor activity of a small-molecule inhibitor of human silent information regulator 2 enzymes.Cancer Res,66(8):4368-4377.https://doi.org/10.1158/0008-5472.can-05-3617
Herranz D,Serrano M,2010.SIRT1:recent lessons from mouse models.Nat Rev Cancer,10(12):819-823.https://doi.org/10.1038/nrc2962
Huang R,Xu YF,Wan W,et al.,2015.Deacetylation of nuclear LC3 drives autophagy initiation under starvation.Mol Cell,57(3):456-466.https://doi.org/10.1016/j.molcel.2014.12.013
Jang KY,Hwang SH,Kwon KS,et al.,2008.SIRT1 expression is associated with poor prognosis of diffuse large B-cell lymphoma.Am J Surg Pathol,32(10):1523-1531.https://doi.org/10.1097/PAS.0b013e31816b6478
Jin YL,Cao Q,Chen C,et al.,2015.Tenovin-6-mediated inhibition of SIRT1/2 induces apoptosis in acute lymphoblastic leukemia(ALL)cells and eliminates ALLstem/progenitor cells.BMC Cancer,15:226.https://doi.org/10.1186/s12885-015-1282-1
Kan YT,Ge P,Wang XY,et al.,2018.SIRT1 rs3758391polymorphism and risk of diffuse large B cell lymphoma in a Chinese population.Cancer Cell Int,18:163.https://doi.org/10.1186/s12935-018-0659-z
Lee IH,Cao L,Mostoslavsky R,et al.,2008.A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy.Proc Natl Acad Sci USA,105(9):3374-3379.https://doi.org/10.1073/pnas.0712145105
Li L,Wang LS,Li L,et al.,2012.Activation of p53 by SIRT1inhibition enhances elimination of CML leukemia stem cells in combination with imatinib.Cancer Cell,21(2):266-281.https://doi.org/10.1016/j.ccr.2011.12.020
Li L,Osdal T,Ho Y,et al.,2014.SIRT1 activation by a c-MYC oncogenic network promotes the maintenance and drug resistance of human FLT3-ITD acute myeloid leukemia stem cells.Cell Stem Cell,15(4):431-446.https://doi.org/10.1016/j.stem.2014.08.001
Li L,Ye SG,Yang M,et al.,2015.SIRT1 downregulation enhances chemosensitivity and survival of adult T-cell leukemia-lymphoma cells by reducing DNA doublestrand repair.Oncol Rep,34(6):2935-2942.https://doi.org/10.3892/or.2015.4287
Luo JY,Nikolaev AY,Imai SI,et al.,2001.Negative control of p53 by Sir2αpromotes cell survival under stress.Cell,107(2):137-148.https://doi.org/10.1016/S0092-8674(01)00524-4
Ng SWK,Mitchell A,Kennedy JA,et al.,2016.A 17-gene stemness score for rapid determination of risk in acute leukaemia.Nature,540(7633):433-437.https://doi.org/10.1038/nature20598
Nihal M,Ahmad N,Wood GS,2014.SIRT1 is upregulated in cutaneous T-cell lymphoma,and its inhibition induces growth arrest and apoptosis.Cell Cycle,13(4):632-640.https://doi.org/10.4161/cc.27523
Ou X,Lee MR,Huang XX,et al.,2014.SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress.Stem Cells,32(5):1183-1194.https://doi.org/10.1002/stem.1641
Patel JP,G?nen M,Figueroa ME,et al.,2012.Prognostic relevance of integrated genetic profiling in acute myeloid leukemia.N Engl J Med,366(12):1079-1089.https://doi.org/10.1056/NEJMoa1112304
Pui CH,Relling MV,Downing JR,2004.Mechanisms of disease:acute lymphoblastic leukemia.N Engl J Med,350(15):1535-1548.https://doi.org/10.1056/NEJMra023001
Quesada AE,Assylbekova B,Jabcuga CE,et al.,2015.Expression of Sirt1 and Fox P3 in classical Hodgkin lymphoma and tumor infiltrating lymphocytes:implications for immune dysregulation,prognosis and potential therapeutic targeting.Int J Clin Exp Pathol,8(10):13241-13248.
Rea D,Mahon FX,2018.How I manage relapse of chronic myeloid leukaemia after stopping tyrosine kinase inhibitor therapy.Br J Haematol,180(1):24-32.https://doi.org/10.1111/bjh.14973
Ren RB,2005.Mechanisms of BCR-ABL in the pathogenesis of chronic myelogenous leukaemia.Nat Rev Cancer,5(3):172-183.https://doi.org/10.1038/nrc1567
Ross DM,Branford S,Seymour JF,et al.,2013.Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease:results from the TWISTER study.Blood,122(4):515-522.https://doi.org/10.1182/blood-2013-02-483750
Roth M,Wang ZQ,Chen WY,2016.SIRT1 and LSD1 competitively regulate KU70 functions in DNA repair and mutation acquisition in cancer cells.Oncotarget,7(31):50195-50214.https://doi.org/10.18632/oncotarget.10328
Sasca D,H?hnel PS,Szybinski J,et al.,2014.SIRT1 prevents genotoxic stress-induced p53 activation in acute myeloid leukemia.Blood,124(1):121-133.https://doi.org/10.1182/blood-2013-11-538819
Sperling AS,Gibson CJ,Ebert BL,2017.The genetics of myelodysplastic syndrome:from clonal haematopoiesis to secondary leukaemia.Nat Rev Cancer,17(1):5-19.https://doi.org/10.1038/nrc.2016.112
Sun J,He X,Zhu YH,et al.,2018.SIRT1 activation disrupts maintenance of myelodysplastic syndrome stem and progenitor cells by restoring TET2 function.Cell Stem Cell,23(3):355-369.e9.https://doi.org/10.1016/j.stem.2018.07.018
Tian WL,Guo R,Wang F,et al.,2018.The IRF9-SIRT1-P53axis is involved in the growth of human acute myeloid leukemia.Exp Cell Res,365(2):185-193.https://doi.org/10.1016/j.yexcr.2018.02.036
Vaziri H,Dessain SK,Ng Eaton E,et al.,2001.hSIR2SIRT1functions as an NAD-dependent p53 deacetylase.Cell,107(2):149-159.https://doi.org/10.1016/S0092-8674(01)00527-X
Wang CG,Chen LH,Hou XH,et al.,2006.Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage.Nat Cell Biol,8(9):1025-1031.https://doi.org/10.1038/ncb1468
Wang RH,Sengupta K,Li CL,et al.,2008.Impaired DNAdamage response,genome instability,and tumorigenesis in SIRT1 mutant mice.Cancer Cell,14(4):312-323.https://doi.org/10.1016/j.ccr.2008.09.001
Wang Z,Yuan H,Roth M,et al.,2013.SIRT1 deacetylase promotes acquisition of genetic mutations for drug resistance in CML cells.Oncogene,32(5):589-598.https://doi.org/10.1038/onc.2012.83
Wang ZQ,Chen CC,Chen WY,2015.CD150-side population defines leukemia stem cells in a BALB/c mouse model of CML and is depleted by genetic loss of SIRT1.Stem Cells,33(12):3437-3451.https://doi.org/10.1002/stem.2218
Yuan HF,Wang ZQ,Li L,et al.,2012.Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis.Blood,119(8):1904-1914.https://doi.org/10.1182/blood-2011-06-361691
Yuan HF,He ML,Cheng F,et al.,2017.Tenovin-6 inhibits proliferation and survival of diffuse large B-cell lymphoma cells by blocking autophagy.Oncotarget,8(9):14912-14924.https://doi.org/10.18632/oncotarget.14741
Zhang WJ,Wu HX,Yang M,et al.,2016.SIRT1 inhibition impairs non-homologous end joining DNA damage repair by increasing Ku70 acetylation in chronic myeloid leukemia cells.Oncotarget,7(12):13538-13550.https://doi.org/10.18632/oncotarget.6455