核糖体DNA转录的表观调控与肿瘤发生
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摘要
近年来,表观遗传机制的研究结果提示核糖体DNA (rDNA)表观调控机制的缺陷可能诱导肿瘤发生。ATRX/DAXX复合物通过介导H3.3的H3K9me3修饰,建立和维持rDNA转录沉默。ATRX/DAXX基因在部分肿瘤中经常发生突变,可能刺激rDNA转录而促进肿瘤发生发展。本文主要阐述rDNA转录表达异常对肿瘤发生的促进作用,介绍rDNA基因转录的表观遗传调控机制,以期为针对rDNA转录调控机制的药物研发提供新的理论支持。
Recent research in epigenetics suggests that defects in epigenetic regulation of ribosomal DNA(r DNA)transcription may contribute to tumorigenesis. ATRX/DAXX complex is involved in the establishment and maintenance of the silence of the rDNA gene through H3K9me3 modification at histone variant H3.3. The ATRX/DAXX-related genes are frequently mutated in some types of tumors, which may increase rDNA transcription and promote cancer development and progression. In this review, we focus on the mechanism that abnormal transcription of rDNA potentially influences tumorigenesis. We also summarize the epigenetic regulatory mechanism of rDNA transcription, which may provide new theoretical support for drug development based on r DNA transcriptional regulation.
Recent research in epigenetics suggests that defects in epigenetic regulation of ribosomal DNA(r DNA)transcription may contribute to tumorigenesis. ATRX/DAXX complex is involved in the establishment and maintenance of the silence of the rDNA gene through H3K9me3 modification at histone variant H3.3. The ATRX/DAXX-related genes are frequently mutated in some types of tumors, which may increase rDNA transcription and promote cancer development and progression. In this review, we focus on the mechanism that abnormal transcription of rDNA potentially influences tumorigenesis. We also summarize the epigenetic regulatory mechanism of rDNA transcription, which may provide new theoretical support for drug development based on r DNA transcriptional regulation.
引文
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[2]Ruggero D,Pandolfi PP.Does the ribosome translate cancer?Nat Rev Cancer,2003,3(3):179-192.
[3]Sulima SO,Hofman IJF,De Keersmaecker K,Dinman JD.How ribosomes translate cancer.Cancer Discov,2017,7(10):1069-1087.
[4]Kopp K,Gasiorowski JZ,Chen D,Gilmore R,Norton JT,Wang C,Leary DJ,Chan EK,Dean DA,Huang S.Pol Itranscription and pre-rRNA processing are coordinated in a transcription-dependent manner in mammalian cells.Mol Biol Cell,2007,18(2):394-403.
[5]Cheng XR,Wei YJ,Huang XW,Wang N,Jiang Q,Liu H,Lei L.Research progress on epigenetic regulation of rDNAtranscription.Progress in Biochemistry and Biophysics,2018,45(5):485-493.程香荣,魏艳军,黄星卫,王楠,姜琦,刘惠,雷蕾.表观调控rDNA转录的研究进展.生物化学与生物物理进展,2018,45(5):485-493.
[6]Grummt I.Wisely chosen paths--regulation of rRNAsynthesis:delivered on 30 june 2010 at the 35th FEBScongress in gothenburg,sweden.The FEBS Journal,2010,277(22):4626-4639.
[7]Derenzini M,Montanaro L,TrerèD.Ribosome biogenesis and cancer.Acta Histochem,2017,119(3):190-197.
[8]Derenzini M.The AgNORs.Micron,2000,31,117-120.
[9]McStay B,Grummt I.The epigenetics of rRNA genes:from molecular to chromosome biology.Annu Rev Cell Dev Bi,2008,24,131-157.
[10]Xie W,Ling T,Zhou Y,Feng W,Zhu Q,Stunnenberg HG,Grummt I,Tao W.The chromatin remodeling complex NuRD establishes the poised state of rRNA genes characterized by bivalent histone modifications and altered nucleosome positions.Proc Natl Acad Sci USA,2012,109(21):8161-8166.
[11]Xu X,Xiong X,Sun Y.The role of ribosomal proteins in the regulation of cell proliferation,tumorigenesis,and genomic integrity.Sci China Life Sci,2016,59(7):656-672.
[12]Warner JR,McIntosh KB.How common are extraribosomal functions of ribosomal proteins?Mol cell,2009,34(1):3-11.
[13]Zhou X,Liao JM,Liao WJ,Lu H.Scission of the p53-MDM2 Loop by ribosomal proteins.Genes Cancer,2012,3(3-4):298-310.
[14]de Las Heras-Rubio A,Perucho L,Paciucci R,Vilardell J,LLeonart ME.Ribosomal proteins as novel players in tumorigenesis.Cancer Metastasis Rev,2014,33(1):115-141.
[15]Thomas G.An encore for ribosome biogenesis in the control of cell proliferation.Nat Cell Biol,2000,2(5):E71-72.
[16]Derenzini M,Montanaro L,ChillàA,Tosti E,Vici M,Barbieri S,Govoni M,Mazzini G,TreréD.Key role of the achievement of an appropriate ribosomal RNAcomplement for G1-S phase transition in H4-II-E-C3 rat hepatoma cells.J Cell Physiol,2005,202(2):483-491.
[17]Zhu J,Blenis J,Yuan J.Activation of PI3K/Akt and MAPK pathways regulates Myc-mediated transcription by phosphorylating and promoting the degradation of Mad1.Proc Natl Acad Sci USA,2008,105(18),6584-6589.
[18]Mayer C,Grummt I.Ribosome biogenesis and cell growth:mTOR coordinates transcription by all three classes of nuclear RNA polymerases.Oncogene,2006,25(48):6384-6391.
[19]Levine AJ.p53,the cellular gatekeeper for growth and division.Cell,1997,88(3):323-331.
[20]Donati G,Bertoni S,Brighenti E,Vici M,TreréD,Volarevic S,Montanaro L,Derenzini M.The balance between rRNA and ribosomal protein synthesis up-and downregulates the tumour suppressor p53 in mammalian cells.Oncogene,2011,30(29):3274-3288.
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[22]Boulon S,Westman BJ,Hutten S,Boisvert FM,Lamond AI.The nucleolus under stress.Mol Cell,2010,40(2):216-227.
[23]Russo A,Russo G.Ribosomal proteins control or bypass p53 during nucleolar stress.Int J Mol Sci,2017,18(1).
[24]Brighenti E,Calabrese C,Liguori G,Giannone FA,TrerèD,Montanaro L,Derenzini M.Interleukin 6downregulates p53 expression and activity by stimulating ribosome biogenesis:a new pathway connecting inflammation to cancer.Oncogene,2014,33(35):4396-4406.
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[26]Giovannucci E,Harlan DM,Archer MC,Bergenstal RM,Gapstur SM,Habel LA,Pollak M,Regensteiner JG,Yee D.Diabetes and cancer:a consensus report.Diabetes Care,2010,33(7):1674-1685.
[27]Candido J,Hagemann T.Cancer-related inflammation.JClin Immunol,2013,33,S79-S84.
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[30]Barlow JL,Drynan LF,Trim NL,Erber WN,Warren AJ,McKenzie AN.New insights into 5q-syndrome as a ribosomopathy.Cell Cycle,2010,9(21):4286-4293.
[31]Doherty L,Sheen MR,Vlachos A,Choesmel V,O'Donohue MF,Clinton C,Schneider HE,Sieff CA,Newburger PE,Ball SE,Niewiadomska E,Matysiak M,Glader B,Arceci RJ,Farrar JE,Atsidaftos E,Lipton JM,Gleizes PE,Gazda HT.Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia.Am JHum Genet,2010,86(2):222-228.
[32]Grummt I.Different epigenetic layers engage in complex crosstalk to define the epigenetic state of mammalian rRNA genes.Hum Mol Genet,2007,16 Spec No 1,R21-27.
[33]Galbiati A,Penzo M,Bacalini MG,Onofrillo C,Guerrieri AN,Garagnani P,Franceschi C,Trere D,Montanaro L.Epigenetic up-regulation of ribosome biogenesis and more aggressive phenotype triggered by the lack of the histone demethylase JHDM1B in mammary epithelial cells.Oncotarget,2017,8(23):37091-37103.
[34]Jiao Y,Shi C,Edil BH,de Wilde RF,Klimstra DS,Maitra A,Schulick RD,Tang LH,Wolfgang CL,Choti MA,Velculescu VE,Diaz LA Jr,Vogelstein B,Kinzler KW,Hruban RH,Papadopoulos N.DAXX/ATRX,MEN1,and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors.Science,2011,331(6021):1199-1203.
[35]Heaphy CM,de Wilde RF,Jiao Y,Klein AP,Edil BH,Shi C,Bettegowda C,Rodriguez FJ,Eberhart CG,Hebbar S,Offerhaus GJ,McLendon R,Rasheed BA,He Y,Yan H,Bigner DD,Oba-Shinjo SM,Marie SK,Riggins GJ,Kinzler KW,Vogelstein B,Hruban RH,Maitra A,Papadopoulos N,Meeker AK.Altered telomeres in tumors with ATRX and DAXX mutations.Science,2011,333(6041):425.
[36]Schwartzentruber J,Korshunov A,Liu XY,Jones DT,Pfaff E,Jacob K,Sturm D,Fontebasso AM,Quang DA,T?njes M,Hovestadt V,Albrecht S,Kool M,Nantel A,Konermann C,Lindroth A,J?ger N,Rausch T,Ryzhova M,Korbel JO,Hielscher T,Hauser P,Garami M,Klekner A,Bognar L,Ebinger M,Schuhmann MU,Scheurlen W,Pekrun A,Frühwald MC,Roggendorf W,Kramm C,Dürken M,Atkinson J,Lepage P,Montpetit A,Zakrzewska M,Zakrzewski K,Liberski PP,Dong Z,Siegel P,Kulozik AE,Zapatka M,Guha A,Malkin D,Felsberg J,Reifenberger G,von Deimling A,Ichimura K,Collins VP,Witt H,Milde T,Witt O,Zhang C,Castelo-Branco P,Lichter P,Faury D,Tabori U,Plass C,Majewski J,Pfister SM,Jabado N.Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.Nature,2012,482(7384):226-231.
[37]Kannan K,Inagaki A,Silber J,Gorovets D,Zhang J,Kastenhuber ER,Heguy A,Petrini JH,Chan TA,Huse JT.Whole-exome sequencing identifies ATRX mutation as a key molecular determinant in lower-grade glioma.Oncotarget,2012,3(10):1194-1203.
[38]Feng Z,Ma J,Hua X.Epigenetic regulation by the menin pathway.Endocrine-Related Cancer,2017,24(10):T147-T159.
[39]Dyer MA,Qadeer ZA,Valle-Garcia D,Bernstein E.ATRXand DAXX:Mechanisms and Mutations.CSH Perspect Med,2017,7(3):DOI:10.1101/cshperspect.a026567.
[40]Goldberg AD,Banaszynski LA,Noh KM,Lewis PW,Elsaesser SJ,Stadler S,Dewell S,Law M,Guo X,Li X,Wen D,Chapgier A,DeKelver RC,Miller JC,Lee YL,Boydston EA,Holmes MC,Gregory PD,Greally JM,Rafii S,Yang C,Scambler PJ,Garrick D,Gibbons RJ,Higgs DR,Cristea IM,Urnov FD,Zheng D,Allis CD.Distinct factors control histone variant H3.3 localization at specific genomic regions.Cell,2010,140(5):678-691.
[41]Huang XW,Cheng XR,Wang N,Zhang YW,Liao C,Jin LH,Lei L.Histone variant H3.3 and its functions in reprogramming.Hereditas(Beijing),2018,40(3):186-196.黄星卫,程香荣,王楠,张雨薇,廖辰,金连弘,雷蕾.组蛋白H3变体H3.3及其在细胞重编程中的作用.遗传,2018,40(3):186-196.
[42]Liu X,Ling ZQ.Role of isocitrate dehydrogenase 1/2(IDH 1/2)gene mutations in human tumors.Histol Histopathol,2015,30(10):1155-1160.
[43]Elsasser SJ,Allis CD,Lewis PW.Cancer.New epigenetic drivers of cancers.Science,2011,331(6021):1145-1146.
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