Aberrant autophagy is a major risk factor for inflammatory diseases and cancer. However, the genetic basis and underlying mechanisms are less established. UVRAG is a tumor suppressor candidate ...involved in autophagy, which is truncated in cancers by a frameshift (FS) mutation and expressed as a shortened UVRAG
. To investigate the role of UVRAG
in vivo, we generated mutant mice that inducibly express UVRAG
(iUVRAG
). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. iUVRAG
mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, iUVRAG
mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant β-catenin stabilization, and centrosome amplification. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.
It is not completely understood how autophagy is tied to inflammation and age-related cancer predisposition. Here, we used a mouse model with inducible expression of a cancer-derived frameshift ...mutation in UV radiation resistance associated (UVRAG) to demonstrate that intervention with autophagy suppressor could exacerbate inflammation and promote age-related spontaneous cancers.
Although alterations of the macroautophagy/autophagy-lysosome pathway have been observed in cancer for many years, the mechanisms underlying these changes and the importance of autophagic and ...lysosomal reprogramming by cancer have yet to be well identified. Our recent study demonstrates that oncogenic BRAF signaling promotes melanoma growth and resistance to BRAF-targeted therapy through phosphorylation and functional inactivation of TFEB (transcription factor EB) and consequent suppression of the autophagy-lysosome gene network. This is by no means the first time that this pathway has been directly linked to oncogenic BRAF-driven melanoma. The key observations revealed in this study also leads to a complex but growing convergence of our understanding of the biology of the autophagy-lysosome pathway and the mechanisms underlying cancer prevention and treatment.
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