ATF4 inhibition by p62 represses stromal metabolic reprogramming and tumorigenesis

Tumors often undergo stress and need to reprogram their metabolism to survive and grow under nutrient challenging conditions. The stroma could play a critical role in this process by providing nutrients or signals to support the epithelial compartment of the tumor. Autophagy has been shown to play key roles both in the stroma and in the epithelium. However, how autophagy adaptors, such as p62, participate in the mechanisms whereby the stroma supports tumor progression is not yet fully understood. Here we show that p62 deficiency in stromal fibroblasts promotes resistance to glutamine deprivation through a metabolic reprogramming orchestrated by the direct control of ATF4 stability by p62-mediated polyubiquitination. This, in turn, activates the flux of glucose carbons through a pyruvate carboxylase-asparagine synthase cascade that results in asparagine-mediated stromal cell growth and tumor epithelial proliferation, independent of autophagy. This supports a new model in which p62 directly targets nuclear transcription factors to control metabolic reprograming in the microenvironment to repress tumorigenesis, and emerges as global tumor suppressor. 52 weeks old p62f/f and p62fspKO prostates were harvested and snap-frozen in dry ice.