Home LiteratureArticle Details
PMID: 17664422 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 104 ·No. 32 ·2007-08-07 ·Pages 13028-33

Wu CH, van Riggelen J, Yetil A, Fan AC, Bachireddy P, Felsher DW

Abstract

Oncogene-induced senescence is an important mechanism by which normal cells are restrained from malignant transformation. Here we report that the suppression of the c-Myc (MYC) oncogene induces cellular senescence in diverse tumor types including lymphoma, osteosarcoma, and hepatocellular carcinoma. MYC inactivation was associated with prototypical markers of senescence, including acidic beta-gal staining, induction of p16INK4a, and p15INK4b expression. Moreover, MYC inactivation induced global changes in chromatin structure associated with the marked reduction of histone H4 acetylation and increased histone H3 K9 methylation. Osteosarcomas engineered to be deficient in p16INK4a or Rb exhibited impaired senescence and failed to exhibit sustained tumor regression upon MYC inactivation. Similarly, only after lymphomas were repaired for p53 expression did MYC inactivation induce robust senescence and sustained tumor regression. The pharmacologic inhibition of signaling pathways implicated in oncogene-induced senescence including ATM/ATR and MAPK did not prevent senescence associated with MYC inactivation. Our results suggest that cellular senescence programs remain latently functional, even in established tumors, and can become reactivated, serving as a critical mechanism of oncogene addiction associated with MYC inactivation.

MeSH Terms
Animals Cellular Senescence Chromatin/chemistry DNA Damage Genes, Retinoblastoma Genes, myc/physiology Genes, p53 Humans MAP Kinase Signaling System Mice Neoplasms/pathology
Chemicals
Chromatin
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Wu Chi-Hwa
Department of Medicine, Division of Oncology, Stanford University School of Medicine, CA 94305, USA.
van Riggelen Jan
Yetil Alper
Fan Alice C
Bachireddy Pavan
Felsher Dean W
References (48)
48 references, click to expand
  1. The p400 E1A-associated protein is a novel component of the p53 --> p21 senescence pathway.
    Genes Dev. 2005 Jan 15;19(2):196-201 PMID: 15655109
  2. Formation of MacroH2A-containing senescence-associated heterochromatin foci and senescence driven by ASF1a and HIRA.
    Dev Cell. 2005 Jan;8(1):19-30 PMID: 15621527
  3. Cancer: crime and punishment.
    Nature. 2005 Aug 4;436(7051):636-7 PMID: 16079829
  4. Tumour biology: senescence in premalignant tumours.
    Nature. 2005 Aug 4;436(7051):642 PMID: 16079833
  5. Oncogene-induced senescence as an initial barrier in lymphoma development.
    Nature. 2005 Aug 4;436(7051):660-5 PMID: 16079837
  6. BRAFE600-associated senescence-like cell cycle arrest of human naevi.
    Nature. 2005 Aug 4;436(7051):720-4 PMID: 16079850
  7. Inhibition of the phosphoinositide 3-kinase pathway induces a senescence-like arrest mediated by p27Kip1.
    J Biol Chem. 2000 Jul 21;275(29):21960-8 PMID: 10791951
  8. Overexpression of MYC causes p53-dependent G2 arrest of normal fibroblasts.
    Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10544-8 PMID: 10962037
  9. Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability.
    Genes Dev. 2000 Oct 1;14(19):2501-14 PMID: 11018017
  10. Repression of p15INK4b expression by Myc through association with Miz-1.
    Nat Cell Biol. 2001 Apr;3(4):392-9 PMID: 11283613
  11. Myc represses the p21(WAF1/CIP1) promoter and interacts with Sp1/Sp3.
    Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4510-5 PMID: 11274368
  12. Regulation of cyclin D2 gene expression by the Myc/Max/Mad network: Myc-dependent TRRAP recruitment and histone acetylation at the cyclin D2 promoter.
    Genes Dev. 2001 Aug 15;15(16):2042-7 PMID: 11511535
  13. Binding of c-Myc to chromatin mediates mitogen-induced acetylation of histone H4 and gene activation.
    Genes Dev. 2001 Aug 15;15(16):2069-82 PMID: 11511539
  14. The myc oncogene: MarvelouslY Complex.
    Adv Cancer Res. 2002;84:81-154 PMID: 11885563
  15. A senescence program controlled by p53 and p16INK4a contributes to the outcome of cancer therapy.
    Cell. 2002 May 3;109(3):335-46 PMID: 12015983
  16. Cancer. Addiction to oncogenes--the Achilles heal of cancer.
    Science. 2002 Jul 5;297(5578):63-4 PMID: 12098689
  17. Sustained loss of a neoplastic phenotype by brief inactivation of MYC.
    Science. 2002 Jul 5;297(5578):102-4 PMID: 12098700
  18. c-MYC: more than just a matter of life and death.
    Nat Rev Cancer. 2002 Oct;2(10):764-76 PMID: 12360279
  19. Role of the Raf/MEK/ERK and the PI3K/Akt(PKB) pathways in fibroblast senescence.
    Exp Gerontol. 2002 Oct-Nov;37(10-11):1149-56 PMID: 12470826
  20. Genomically complex lymphomas undergo sustained tumor regression upon MYC inactivation unless they acquire novel chromosomal translocations.
    Blood. 2003 Apr 1;101(7):2797-803 PMID: 12517816
  21. Cancer revoked: oncogenes as therapeutic targets.
    Nat Rev Cancer. 2003 May;3(5):375-80 PMID: 12724735
  22. Genomic targets of the human c-Myc protein.
    Genes Dev. 2003 May 1;17(9):1115-29 PMID: 12695333
  23. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence.
    Cell. 2003 Jun 13;113(6):703-16 PMID: 12809602
  24. Werner syndrome protein limits MYC-induced cellular senescence.
    Genes Dev. 2003 Jul 1;17(13):1569-74 PMID: 12842909
  25. Myc: a weapon of mass destruction.
    Cell. 2004 Apr 16;117(2):153-6 PMID: 15084254
  26. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer.
    Nature. 2004 Oct 28;431(7012):1112-7 PMID: 15475948
  27. A biomarker that identifies senescent human cells in culture and in aging skin in vivo.
    Proc Natl Acad Sci U S A. 1995 Sep 26;92(20):9363-7 PMID: 7568133
  28. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a.
    Cell. 1997 Mar 7;88(5):593-602 PMID: 9054499
  29. Senescence of human fibroblasts induced by oncogenic Raf.
    Genes Dev. 1998 Oct 1;12(19):2997-3007 PMID: 9765202
  30. c-Myc target genes involved in cell growth, apoptosis, and metabolism.
    Mol Cell Biol. 1999 Jan;19(1):1-11 PMID: 9858526
  31. Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine.
    Cancer Res. 1999 Sep 1;59(17):4375-82 PMID: 10485486
  32. Reversible tumorigenesis by MYC in hematopoietic lineages.
    Mol Cell. 1999 Aug;4(2):199-207 PMID: 10488335
  33. Intrinsic tumour suppression.
    Nature. 2004 Nov 18;432(7015):307-15 PMID: 15549092
  34. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis.
    Nature. 2005 Aug 4;436(7051):725-30 PMID: 16079851
  35. Pak4 induces premature senescence via a pathway requiring p16INK4/p19ARF and mitogen-activated protein kinase signaling.
    Mol Cell Biol. 2005 Nov;25(21):9532-42 PMID: 16227603
  36. Reduced c-Myc signaling triggers telomere-independent senescence by regulating Bmi-1 and p16(INK4a).
    Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3645-50 PMID: 16537449
  37. Myc influences global chromatin structure.
    EMBO J. 2006 Jun 21;25(12):2723-34 PMID: 16724113
  38. Skin epidermis lacking the c-Myc gene is resistant to Ras-driven tumorigenesis but can reacquire sensitivity upon additional loss of the p21Cip1 gene.
    Genes Dev. 2006 Aug 1;20(15):2024-9 PMID: 16882980
  39. The c-Myc target gene network.
    Semin Cancer Biol. 2006 Aug;16(4):253-64 PMID: 16904903
  40. Sustained regression of tumors upon MYC inactivation requires p53 or thrombospondin-1 to reverse the angiogenic switch.
    Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16266-71 PMID: 17056717
  41. A common signaling cascade may underlie "addiction" to the Src, BCR-ABL, and EGF receptor oncogenes.
    Cancer Cell. 2006 Nov;10(5):425-35 PMID: 17097564
  42. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.
    Nature. 2006 Nov 30;444(7119):633-7 PMID: 17136093
  43. Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication.
    Nature. 2006 Nov 30;444(7119):638-42 PMID: 17136094
  44. A negative feedback signaling network underlies oncogene-induced senescence.
    Cancer Cell. 2006 Dec;10(6):459-72 PMID: 17157787
  45. HIF1alpha delays premature senescence through the activation of MIF.
    Genes Dev. 2006 Dec 15;20(24):3366-71 PMID: 17142669
  46. Restoration of p53 function leads to tumour regression in vivo.
    Nature. 2007 Feb 8;445(7128):661-5 PMID: 17251932
  47. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas.
    Nature. 2007 Feb 8;445(7128):656-60 PMID: 17251933
  48. Transcriptional regulation and transformation by Myc proteins.
    Nat Rev Mol Cell Biol. 2005 Aug;6(8):635-45 PMID: 16064138
Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.0701953104
Published
2007-08-07
Epub
2007-00-30
Pages
13028-33
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC1941831
Subset
IM
Grants
NCI NIH HHS · U56 CA112973 · United States
NCI NIH HHS · 1P20 CA112973 · United States
NCI NIH HHS · R01 CA089305 · United States
NCI NIH HHS · R01 CA105102 · United States
NCI NIH HHS · 3R01CA089305-03S1 · United States
NCI NIH HHS · R01 CA085610 · United States
NCI NIH HHS · R01-CA85610 · United States
NCI NIH HHS · R01-CA105102 · United States
External Links
PubMed source DOI: 10.1073/pnas.0701953104 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2