AMBRA1-mediated regulation of C-MYC and its relevance to cancer

When coping with nutrient shortage and cellular stressors, cells simultaneously induce autophagy and inhibit cell proliferation in order to attempt to preserve homeostasis and energy balance. Although the interplay between autophagy and cell proliferation is known to be relevant to both physiology and human diseases, very few molecules coordinating these two pathways have been identified so far. Notably, in a recent work, we introduced AMBRA1 as a key molecule in the crosstalk between autophagy and cell proliferation. In particular, we finely characterized AMBRA1 role in the modulation of C-MYC phosphorylation and stability, an event driving both cell proliferation and oncogenesis. Consistently, AMBRA1 is a haploinsufficient tumor suppressor gene, and its alterations are associated with human cancers, thus strongly supporting the relevance of the AMBRA1-mediated regulation of C-MYC in tumorigenesis. Hence, it is important to control AMBRA1 levels/activity in normal cells, in order to prevent transformation. Indeed, AMBRA1 is in an intricate relationship with regulators of autophagy and cell proliferation, establishing feedback loops and parallel/epistatic regulations. All of this evidence and its relevance to cancer and cancer-treatment strategies are discussed in this chapter.