Regulation of p53 and Rb Links the Alternative NF-κB Pathway to EZH2 Expression and Cell Senescence

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Although the classical NF-κB pathway is frequently associated with the induction of cellular senescence and the senescence associated secretory phenotype (SASP), the role of the alternative NF-κB pathway, which is frequently activated in hematological malignancies as well as some solid tumors, has not been defined. We therefore investigated the role of the alternative NF-κB pathway in this process. Here we report that NF-κB2 and RelB, the effectors of the alternative NF-κB pathway, suppress senescence through inhibition of p53 activity. Using primary human fibroblasts, we demonstrate that this is accomplished through NF-κB2/RelB dependent control of a previously unknown pathway, incorporating regulation of CDK4 and 6 expression as well as regulators of p21WAF1 and p53 protein stability. Loss of NF-κB2/RelB results in suppression of retinoblastoma (Rb) tumour suppressor phosphorylation, which in turn leads to inhibition of EZH2 expression and de-repression of p53 activity. Interestingly, we find that CD40 ligand stimulation of cells from Chronic Lymphocytic Leukemia patients, which strongly induces the alternative NF-κB pathway, also induces EZH2 expression. We propose that the alternative NF-κB pathway can promote tumorigenesis through suppression of p53 dependent senescence, a process that may have relevance to cancer cells retaining wild type p53.

Vyšlo v časopise: Regulation of p53 and Rb Links the Alternative NF-κB Pathway to EZH2 Expression and Cell Senescence. PLoS Genet 10(9): e32767. doi:10.1371/journal.pgen.1004642
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004642

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Zdroje

1. HaydenMS, GhoshS (2008) Shared principles in NF-κB signaling. Cell 132 : 344–362.

2. PerkinsND (2007) Integrating cell-signalling pathways with NF-κB and IKK function. Nat Rev Mol Cell Biol 8 : 49–62.

3. Ben-NeriahY, KarinM (2011) Inflammation meets cancer, with NF-κB as the matchmaker. Nat Immunol 12 : 715–723.

4. PerkinsND (2012) The diverse and complex roles of NF-κB subunits in cancer. Nat Rev Cancer 12 : 121–132.

5. VaughanS, JatPS (2011) Deciphering the role of nuclear factor-κB in cellular senescence. Aging 3 : 913–919.

6. ChienY, ScuoppoC, WangX, FangX, BalgleyB, et al. (2011) Control of the senescence-associated secretory phenotype by NF-κB promotes senescence and enhances chemosensitivity. Genes Dev 25 : 2125–2136.

7. JingH, KaseJ, DorrJR, MilanovicM, LenzeD, et al. (2011) Opposing roles of NF-κB in anti-cancer treatment outcome unveiled by cross-species investigations. Genes Dev

8. SfikasA, BatsiC, TselikouE, VartholomatosG, MonokrousosN, et al. (2012) The canonical NF-κB pathway differentially protects normal and human tumor cells from ROS-induced DNA damage. Cellular Signalling 24 : 2007–2023.

9. DeyA, TergaonkarV, LaneDP (2008) Double-edged swords as cancer therapeutics: simultaneously targeting p53 and NF-κB pathways. Nat Rev Drug Discov 7 : 1031–1040.

10. AkP, LevineAJ (2010) p53 and NF-κB: different strategies for responding to stress lead to a functional antagonism. FASEB J 24 : 3643–3652.

11. SchneiderG, KramerOH (2011) NFκB/p53 crosstalk-a promising new therapeutic target. Biochim Biophys Acta 1815 : 90–103.

12. VigneronA, VousdenKH (2010) p53, ROS and senescence in the control of aging. Aging (Albany NY) 2 : 471–474.

13. RochaS, MartinAM, MeekDW, PerkinsND (2003) p53 represses cyclin D1 transcription through down regulation of Bcl-3 and inducing increased association of the p52 NF-κB subunit with histone deacetylase 1. Mol Cell Biol 23 : 4713–4727.

14. SchummK, RochaS, CaamanoJ, PerkinsND (2006) Regulation of p53 tumour suppressor target gene expression by the p52 NF-κB subunit. EMBO J 25 : 4820–4832.

15. ShettyS, GrahamBA, BrownJG, HuX, Vegh-YaremaN, et al. (2005) Transcription factor NF-κB differentially regulates death receptor 5 expression involving histone deacetylase 1. Mol Cell Biol 25 : 5404–5416.

16. FrankAK, LeuJI, ZhouY, DevarajanK, NedelkoT, et al. (2011) The codon 72 polymorphism of p53 regulates interaction with NF-κB and transactivation of genes involved in immunity and inflammation. Mol Cell Biol 31 : 1201–1213.

17. De SantaF, NarangV, YapZH, TusiBK, BurgoldT, et al. (2009) Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. EMBO J 28 : 3341–3352.

18. TangX, MilyavskyM, ShatsI, ErezN, GoldfingerN, et al. (2004) Activated p53 suppresses the histone methyltransferase EZH2 gene. Oncogene 23 : 5759–5769.

19. BrackenAP, PasiniD, CapraM, ProsperiniE, ColliE, et al. (2003) EZH2 is downstream of the pRB-E2F pathway, essential for proliferation and amplified in cancer. EMBO J 22 : 5323–5335.

20. ChaseA, CrossNC (2011) Aberrations of EZH2 in cancer. Clin Cancer Res 17 : 2613–2618.

21. BrackenAP, Kleine-KohlbrecherD, DietrichN, PasiniD, GargiuloG, et al. (2007) The Polycomb group proteins bind throughout the INK4A-ARF locus and are disassociated in senescent cells. Genes Dev 21 : 525–530.

22. FanT, JiangS, ChungN, AlikhanA, NiC, et al. (2011) EZH2-dependent suppression of a cellular senescence phenotype in melanoma cells by inhibition of p21/CDKN1A expression. Mol Cancer Res 9 : 418–429.

23. TzatsosA, PaskalevaP, LymperiS, ContinoG, StoykovaS, et al. (2011) Lysine-specific demethylase 2B (KDM2B)-let-7-enhancer of zester homolog 2 (EZH2) pathway regulates cell cycle progression and senescence in primary cells. J Biol Chem 286 : 33061–33069.

24. MargueronR, ReinbergD (2011) The Polycomb complex PRC2 and its mark in life. Nature 469 : 343–349.

25. LaniganF, GeraghtyJG, BrackenAP (2011) Transcriptional regulation of cellular senescence. Oncogene 30 : 2901–2911.

26. LeeST, LiZ, WuZ, AauM, GuanP, et al. (2011) Context-Specific Regulation of NF-κB Target Gene Expression by EZH2 in Breast Cancers. Mol Cell 43 : 798–810.

27. GuoZ, KozlovS, LavinMF, PersonMD, PaullTT (2010) ATM activation by oxidative stress. Science 330 : 517–521.

28. ShihVF, Davis-TurakJ, MacalM, HuangJQ, PonomarenkoJ, et al. (2012) Control of RelB during dendritic cell activation integrates canonical and noncanonical NF-κB pathways. Nat Immunol 13 : 1162–1170.

29. PepperC, MahdiJG, BugginsAG, HewamanaS, WalsbyE, et al. (2011) Two novel aspirin analogues show selective cytotoxicity in primary chronic lymphocytic leukaemia cells that is associated with dual inhibition of Rel A and COX-2. Cell Prolif 44 : 380–390.

30. HostagerBS, BishopGA (2013) CD40-Mediated Activation of the NF-κB2 Pathway. Front Immunol 4 : 376.

31. FreundA, LabergeRM, DemariaM, CampisiJ (2012) Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell 23 : 2066–2075.

32. RovillainE, MansfieldL, CaetanoC, Alvarez-FernandezM, CaballeroOL, et al. (2011) Activation of Nuclear Factor-κB signalling promotes cellular senescence. Oncogene 30 : 2356–2366.

33. KavanaughGM, Wise-DraperTM, MorrealeRJ, MorrisonMA, GoleB, et al. (2011) The human DEK oncogene regulates DNA damage response signaling and repair. Nucleic Acids Res 39 : 7465–7476.

34. LiuK, FengT, LiuJ, ZhongM, ZhangS (2012) Silencing of the DEK gene induces apoptosis and senescence in CaSki cervical carcinoma cells via the up-regulation of NF-κB p65. Biosci Rep 32 : 323–332.

35. RaptisL, ArulanandamR, GeletuM, TurksonJ (2011) The R(h)oads to Stat3: Stat3 activation by the Rho GTPases. Exp Cell Res 317 : 1787–1795.

36. ChengG, DieboldBA, HughesY, LambethJD (2006) Nox1-dependent reactive oxygen generation is regulated by Rac1. J Biol Chem 281 : 17718–17726.

37. QianY, LiuKJ, ChenY, FlynnDC, CastranovaV, et al. (2005) Cdc42 regulates arsenic-induced NADPH oxidase activation and cell migration through actin filament reorganization. J Biol Chem 280 : 3875–3884.

38. PolagerS, GinsbergD (2008) E2F -⁠ at the crossroads of life and death. Trends Cell Biol 18 : 528–535.

39. LedouxAC, SellierH, GilliesK, IannettiA, JamesJ, et al. (2013) NFκB regulates expression of Polo-like kinase 4. Cell Cycle 12 : 3052–3062.

40. ZhaoB, BarreraLA, ErsingI, WilloxB, SchmidtSCS, et al. (2014) The NF-κB Genomic Landscape in Lymphoblastoid B-cells. Cell Reports In Press.

41. TergaonkarV, PandoM, VafaO, WahlG, VermaI (2002) p53 stabilization is decreased upon NFκB activation: a role for NFκB in acquisition of resistance to chemotherapy. Cancer Cell 1 : 493–503.

42. ArltA, SebensS, KrebsS, GeismannC, GrossmannM, et al. (2013) Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene 32 : 4825–4835.

43. SongMS, CarracedoA, SalmenaL, SongSJ, EgiaA, et al. (2011) Nuclear PTEN regulates the APC-CDH1 tumor-suppressive complex in a phosphatase-independent manner. Cell 144 : 187–199.

44. VuD, HuangDB, VemuA, GhoshG (2013) A structural basis for selective dimerization by NF-κB RelB. J Mol Biol 425 : 1934–1945.

45. AnnunziataCM, DavisRE, DemchenkoY, BellamyW, GabreaA, et al. (2007) Frequent engagement of the classical and alternative NF-κB pathways by diverse genetic abnormalities in multiple myeloma. Cancer Cell 12 : 115–130.

46. DemchenkoYN, GlebovOK, ZingoneA, KeatsJJ, BergsagelPL, et al. (2010) Classical and/or alternative NF-κB pathway activation in multiple myeloma. Blood 115 : 3541–3552.

47. GilmoreTD (2007) Multiple myeloma: lusting for NF-κB. Cancer Cell 12 : 95–97.

48. MigliazzaA, LombardiL, RocchiM, TreccaD, ChangCC, et al. (1994) Heterogeneous chromosomal aberrations generate 3′ truncations of the NFKB2/lyt-10 gene in lymphoid malignancies. Blood 84 : 3850–3860.

49. ThakurS, LinH, TsengW, KumarS, BravoR, et al. (1994) Rearrangement and altered expression of the NFKB-2 gene in human cutaneous T-lymphoma cells. Oncogene 9 : 2335–2344.

50. Homig-HolzelC, HojerC, RastelliJ, CasolaS, StroblLJ, et al. (2008) Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-κB pathway and promotes lymphomagenesis. J Exp Med 205 : 1317–1329.

51. PospisilovaS, GonzalezD, MalcikovaJ, TrbusekM, RossiD, et al. (2012) ERIC recommendations on TP53 mutation analysis in chronic lymphocytic leukemia. Leukemia 26 : 1458–1461.

52. BeguelinW, PopovicR, TeaterM, JiangY, BuntingKL, et al. (2013) EZH2 Is Required for Germinal Center Formation and Somatic EZH2 Mutations Promote Lymphoid Transformation. Cancer Cell 23 : 677–692.

53. BraunT, CarvalhoG, FabreC, GrosjeanJ, FenauxP, et al. (2006) Targeting NF-κB in hematologic malignancies. Cell Death Differ 13 : 748–758.

54. FuchsO (2010) Transcription factor NF-κB inhibitors as single therapeutic agents or in combination with classical chemotherapeutic agents for the treatment of hematologic malignancies. Curr Mol Pharmacol 3 : 98–122.

55. KeutgensA, RobertI, ViatourP, ChariotA (2006) Deregulated NF-κB activity in haematological malignancies. Biochem Pharmacol 72 : 1069–1080.

56. DuP, KibbeWA, LinSM (2008) lumi: a pipeline for processing Illumina microarray. Bioinformatics 24 : 1547–1548.

57. GentlemanRC, CareyVJ, BatesDM, BolstadB, DettlingM, et al. (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5: R80.

58. Smyth GK (2005) Limma: linear models for microarray data. In: Gentleman RC, Carey VJ, Dudoit S, Irizarry R, Huber W, editors. ‘Bioinformatics and Computational Biology Solutions using R and Bioconductor. New York: Springer. pp. 397–420.

59. DimriGP, LeeX, BasileG, AcostaM, ScottG, et al. (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92 : 9363–9367.

60. LyonsAB, ParishCR (1994) Determination of lymphocyte division by flow cytometry. J Immunol Methods 171 : 131–137.

61. PfafflMW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29: e45.

62. LangmeadB, TrapnellC, PopM, SalzbergSL (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10: R25.

63. RobinsonJT, ThorvaldsdottirH, WincklerW, GuttmanM, LanderES, et al. (2011) Integrative genomics viewer. Nat Biotechnol 29 : 24–26.

64. RooneyI, ButrovichK, WareCF (2000) Expression of lymphotoxins and their receptor-Fc fusion proteins by baculovirus. Methods Enzymol 322 : 345–363.