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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.

Ultraviolet radiation (UVR)-induced skin pigmentation, afforded by the dark organelles termed melanosomes, accounts for the first-line protection against environmental UVR that increases the risk of developing skin cancers including melanoma. We have recently discovered that UVRAG, originally identified as a BECN1-binding macroautophagy/autophagy protein, appears to have a specialized function in melanosome biogenesis beyond autophagy through its interaction with the biogenesis of lysosome-related organelles complex 1 (BLOC-1). This melanogenic function of UVRAG is controlled by the melanocyte-specific transcription factor MITF as a downstream effector of the α-melanocyte-stimulating hormone (α-MSH)-cAMP signaling in the suntan response, which is compromised in BRAF mutant melanoma. Thus we propose a new mode of UVRAG activity and regulation in melanocyte biology that may affect melanoma predisposition.

Ultraviolet (UV)-induced DNA damage is a major risk factor for skin cancers including melanoma. UVRAG, originally identified to complement UV sensitivity in xeroderma pigmentosum (XP), has since been implicated in modulating macroautophagy/autophagy, in coordinating different intracellular trafficking pathways, and in maintaining chromosomal stability. Intriguingly, our recent study has demonstrated that UVRAG plays an essential role in protecting cells from UV-induced DNA damage by activating the nucleotide excision repair (NER) pathway. Since NER is the major mechanism by which cells maintain DNA integrity against UV insult, the inactivation of UVRAG seen in some melanoma may impart these cells with an ability to accumulate high-load UV mutagenesis, leading to cancer progression. Thus, this property of UVRAG has untapped potential to be of fundamental importance in understanding the genetics and pathogenesis of human skin cancer.