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

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 ␤-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.oncogene addiction ͉ tumorigenesis ͉ tumor maintenance

Actions of human telomerase beyond telomeres

“…Consistent with the two-step hypothesis for senescence and immortalization [7], It has been experimentally shown that senescence is not only a potent defense against cancer [9][10][11][12][13][14], but that cancer cells that have escaped senescence can be reversed to senescence by restoration of the tumor suppressor p53 [15,16]. It is thus widely believed that senescence and immortalization share some common biology, and telomeres and telomerase may be the connection [17].…”

Long-distance interaction of the integrated HPV fragment with MYC gene and 8q24.22 region upregulating the allele-specific MYC expression in HeLa cells

“…Consistently, we observed that HeLa cells occurred senescence when the integrated HPV fragment was removed. Considering the phenomenon that the expression of MYC was dramatically reduced when the HPV knockout, we postulated that the cell senescence might be related to the significant downregulation of MYC expression, which had been proved to play a crucial role of integrated HPV in cervical cancer cell growth 17. But we also noticed that the double knockout of 8q24.22 region could not induce obvious senescence in HeLa cells, although it lead to about 50% decrease of MYC expression.…”

Cristacarpin promotes ER stress-mediated ROS generation leading to premature senescence by activation of p21waf-1

“…Hydroxyurea, resveratrol, and pyrithione induce premature senescence by ROS generation (Luo et al 2013;Ong et al 2011). Thus, drug targeting premature senescence in cancer cells could be a superior approach rather activating apoptosis because at a lower concentration of the drug, activated senescence regresses the tumor growth by neutralizing the toxicity of the drugs (Wu et al 2007). Of note, senescence can be an alternative route to curb tumor growth where cells get resistance to apoptosis.…”