Importance de la voie Cdk4-EZH2 dans l'échappement à la sénescence induite par la chimiothérapie

Abstract : Chemotherapy-induced senescence enables to trigger a durable division arrest of tumor cells. However, this tumor suppressor mechanism is neutralized in some treated cells leading mostly to cancer relapse in patients. Recently, we have described a MCL1-dependent mechanism of escape in SN-38-induced senescence from colorectal cell lines. In this study, we showed that senescent cells (PLS cells) promoted the non senescent cells (PLD cells) proliferation through mitogenic signals stimulating Cdk4 kinase activity and subsequently the cell cycle. We demonstrated that Cdk4 phosphorylated Rb on the serine 780 to inhibit its activity, allowing E2F- family transcriptional functions activation on cell cycle targets. Loss of Cdk4 expression or activity induced by RNA interference or Palbociclib reduced the emergence of proliferating clones. TheEZH2-methyltransferase, a E2F transcriptional target, is only expressed by PLD cells and this expression depends on Cdk4 activity. Moreover, loss of EZH2 expression or activity, by RNA interference or by DZNepA and GSK343 inhibitors, reduced the emergence of proliferating cells. Finally, EZH2 inhibition promotes both cell division arrest and senescence in response to Palbociclibin the SN-38-escaped cells. To conclude, this study enabled to highlight a major role of EZH2 as effector of Cdk4 in the escape mechanism induced by SN-38 a signaling pathway offering newtargeted cancer therapies.
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Julien Gouju. Importance de la voie Cdk4-EZH2 dans l'échappement à la sénescence induite par la chimiothérapie. Médecine humaine et pathologie. Université d'Angers, 2016. Français. ⟨NNT : 2016ANGE0056⟩. ⟨tel-02276048⟩

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