Wu CH, van Riggelen J, Yetil A, Fan AC, Bachireddy P, Felsher DW.. Cellular senescence is an important mechanism of tumor regression upon c-Myc inactivation. Proc Natl Acad Sci USA 104: 13028-13033

Department of Medicine, Division of Oncology, Stanford University School of Medicine, CA 94305, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 09/2007; 104(32):13028-33. DOI: 10.1073/pnas.0701953104
Source: PubMed


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.

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    • "Our study also explores the causes underlying the differential MYC requirement in cancer (von Eyss and Eilers, 2011). Prior work has emphasized MYC's role maintaining angiogenesis (Sodir et al., 2011) and its ability to restrain cellular senescence or differentiation (Lin et al., 2009; Varlakhanova et al., 2011; Wu et al., 2007). Our results indicate that the differential MYC requirement reflects, at least in part, the need to maintain the expression of the cancer-specific isoforms of pyruvate kinase (PKM2) and lactate dehydrogenase (LDH-A) (Christofk et al., 2008; Clower et al., 2010; David et al., 2010; Shim et al., 1997; Vander Heiden et al., 2009). "
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