The E6-Associated Protein (E6AP) is known for its role in promoting p53 for degradation in HPV-infected cells. We have recently revealed a novel function of E6AP in the regulation of cellular senescence in mouse embryonic fibroblasts (MEFs) by modulating the p53 pathway. E6AP deficient MEFs bypass oncogene- and stress-induced senescence and display accelerated tumourigenesis in transplanted mice. In a search for a molecular explanation for this impairment, we found that in E6AP knockout MEFs the expression of the tumour suppressors encoded by the INK4/ARF locus is reduced. A mechanistic explanation for the regulation of the INK4/ARF locus by E6AP, which controls cellular senescence via the p16-pRb and p53 pathways, will be presented. To examine the relevance of our findings to human cancer we chose non-small cell lung cancer (NSCLC) as a cancer model, in which the p16 gene is frequently silenced. We found that the regulation of cellular senescence by E6AP occurs in a cohort of NSCLC patients and correlates to poor survival. Overall, our study explores a new pathway to the silencing of the INK4/ARF locus, which provides an explanation for how E6AP controls cellular senescence via the p16-pRb and p53 pathways.