Reassembly of Nucleosomes at the Promoter Initiates Resilencing Following Decitabine Exposure

English version České info

Hypomethylating agents reactivate tumor suppressor genes that are epigenetically silenced in cancer. Inevitably these genes are resilenced, leading to drug resistance. Using the MLH1 tumor suppressor gene as a model, we showed that decitabine-induced re-expression was dependent upon demethylation and eviction of promoter nucleosomes. Following decitabine withdrawal, MLH1 was rapidly resilenced despite persistent promoter demethylation. Single molecule analysis at multiple time points showed that gene resilencing was initiated by nucleosome reassembly on demethylated DNA and only then was followed by remethylation and stable silencing. Taken together, these data establish the importance of nucleosome positioning in mediating resilencing of drug-induced gene reactivation and suggest a role for therapeutic targeting of nucleosome assembly as a mechanism to overcome drug resistance.

Vyšlo v časopise: Reassembly of Nucleosomes at the Promoter Initiates Resilencing Following Decitabine Exposure. PLoS Genet 9(7): e32767. doi:10.1371/journal.pgen.1003636
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003636

Souhrn

Zdroje

1. CowanLA, TalwarS, YangAS (2010) Will DNA methylation inhibitors work in solid tumors? A review of the clinical experience with azacitidine and decitabine in solid tumors. Epigenomics 2: 71–86.

2. HackansonB, RobbelC, WijermansP, LubbertM (2005) In vivo effects of decitabine in myelodysplasia and acute myeloid leukemia: review of cytogenetic and molecular studies. Ann Hematol 84 Suppl 1: 32–38.

3. GoodyearO, AgathanggelouA, Novitzky-BassoI, SiddiqueS, McSkeaneT, et al. (2010) Induction of a CD8+ T-cell response to the MAGE cancer testis antigen by combined treatment with azacitidine and sodium valproate in patients with acute myeloid leukemia and myelodysplasia. Blood 116: 1908–1918.

4. DaskalakisM, NguyenTT, NguyenC, GuldbergP, KohlerG, et al. (2002) Demethylation of a hypermethylated P15/INK4B gene in patients with myelodysplastic syndrome by 5-Aza-2′-deoxycytidine (decitabine) treatment. Blood 100: 2957–2964.

5. BlumW, KlisovicRB, HackansonB, LiuZ, LiuS, et al. (2007) Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 25: 3884–3891.

6. TsaiHC, LiH, Van NesteL, CaiY, RobertC, et al. (2012) Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 21: 430–446.

7. PrebetT, GoreSD, EsterniB, GardinC, ItzyksonR, et al. (2011) Outcome of high-risk myelodysplastic syndrome after azacitidine treatment failure. J Clin Oncol 29: 3322–3327.

8. QinT, JelinekJ, SiJ, ShuJ, IssaJP (2009) Mechanisms of resistance to 5-aza-2′-deoxycytidine in human cancer cell lines. Blood 113: 659–667.

9. QinT, CastoroR, El AhdabS, JelinekJ, WangX, et al. (2011) Mechanisms of resistance to decitabine in the myelodysplastic syndrome. PLoS One 6: e23372.

10. KageyJD, Kapoor-VaziraniP, McCabeMT, PowellDR, VertinoPM (2010) Long-term stability of demethylation after transient exposure to 5-aza-2′-deoxycytidine correlates with sustained RNA polymerase II occupancy. Mol Cancer Res 8: 1048–1059.

11. WongCM, WongCC, NgYL, AuSL, KoFC, et al. (2011) Transcriptional repressive H3K9 and H3K27 methylations contribute to DNMT1-mediated DNA methylation recovery. PLoS One 6: e16702.

12. EggerG, AparicioAM, EscobarSG, JonesPA (2007) Inhibition of histone deacetylation does not block resilencing of p16 after 5-aza-2′-deoxycytidine treatment. Cancer Res 67: 346–353.

13. SiJ, BoumberYA, ShuJ, QinT, AhmedS, et al. (2010) Chromatin remodeling is required for gene reactivation after decitabine-mediated DNA hypomethylation. Cancer Res 70: 6968–6977.

14. LinJC, JeongS, LiangG, TakaiD, FatemiM, et al. (2007) Role of nucleosomal occupancy in the epigenetic silencing of the MLH1 CpG island. Cancer Cell 12: 432–444.

15. DengG, ChenA, HongJ, ChaeHS, KimYS (1999) Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. Cancer Res 59: 2029–2033.

16. KolodnerRD (1995) Mismatch repair: mechanisms and relationship to cancer susceptibility. Trends Biochem Sci 20: 397–401.

17. HitchinsMP, RapkinsRW, KwokCT, SrivastavaS, WongJJ, et al. (2011) Dominantly inherited constitutional epigenetic silencing of MLH1 in a cancer-affected family is linked to a single nucleotide variant within the 5′UTR. Cancer Cell 20: 200–213.

18. YouJS, KellyTK, De CarvalhoDD, TaberlayPC, LiangG, et al. (2011) OCT4 establishes and maintains nucleosome-depleted regions that provide additional layers of epigenetic regulation of its target genes. Proc Natl Acad Sci U S A 108: 14497–14502.

19. VermeulenM, MulderKW, DenissovS, PijnappelWW, van SchaikFM, et al. (2007) Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131: 58–69.

20. OoiSK, QiuC, BernsteinE, LiK, JiaD, et al. (2007) DNMT3L connects unmethylated lysine 4 of histone H3 to de novo methylation of DNA. Nature 448: 714–717.

21. RodriguezJ, MunozM, VivesL, FrangouCG, GroudineM, et al. (2008) Bivalent domains enforce transcriptional memory of DNA methylated genes in cancer cells. Proc Natl Acad Sci U S A 105: 19809–19814.

22. TakeshimaH, YamashitaS, ShimazuT, NiwaT, UshijimaT (2009) The presence of RNA polymerase II, active or stalled, predicts epigenetic fate of promoter CpG islands. Genome Res 19: 1974–1982.

23. GoelA, NguyenTP, LeungHC, NagasakaT, RheesJ, et al. (2011) De novo constitutional MLH1 epimutations confer early-onset colorectal cancer in two new sporadic Lynch syndrome cases, with derivation of the epimutation on the paternal allele in one. Int J Cancer 128: 869–878.

24. QuinlivanEP, GregoryJF3rd (2008) DNA methylation determination by liquid chromatography-tandem mass spectrometry using novel biosynthetic [U-15N]deoxycytidine and [U-15N]methyldeoxycytidine internal standards. Nucleic Acids Res 36: e119.

25. LiuJ, HessonLB, MeagherAP, BourkeMJ, HawkinsNJ, et al. (2012) Relative distribution of folate species is associated with global DNA methylation in human colorectal mucosa. Cancer Prev Res (Phila) 5: 921–929.

26. ReghaK, SloaneMA, HuangR, PaulerFM, WarczokKE, et al. (2007) Active and repressive chromatin are interspersed without spreading in an imprinted gene cluster in the mammalian genome. Mol Cell 27: 353–366.

27. KellyTK, MirandaTB, LiangG, BermanBP, LinJC, et al. (2010) H2A.Z maintenance during mitosis reveals nucleosome shifting on mitotically silenced genes. Mol Cell 39: 901–911.