Autophagy suppresses melanoma tumorigenesis by inducing senescence

Abstract

Whether and how autophagy is involved in tumorigenesis is poorly understood. We approached this question by investigating a relatively large cohort of patients with mostly early primary melanoma for their expression of 2 markers for autophagy, the protein ATG5 (autophagy-related 5) and MAP1LC3B/LC3 (microtubule-associated protein 1 light chain 3B). Surprisingly, we discovered that both ATG5 and LC3 levels are decreased in patients with melanomas as compared with those with benign nevi. We wondered why reduced autophagy should facilitate early tumor development. Using an in vitro model of melanoma tumorigenesis, in which a mutated oncogene, BRAF (v-raf murine sarcoma viral oncogene homolog B), had been introduced into normal human melanocytes, we were able to show that downregulation of ATG5 promoted the proliferation of melanocytes because it facilitated bypassing oncogene-induced senescence (OIS). Our work supports previous reports that had argued that autophagy actually suppresses tumorigenesis and explains the possible mechanism. Furthermore, our findings suggest that the status of ATG5 and autophagy could serve as a diagnostic marker for distinguishing benign from malignant tumors of melanocytes.

Keywords: ATG5; autophagy; epigenetics; melanoma; promoter methylation; senescence.

Figure 1. A deficiency in ATG5 expression and autophagy promotes melanoma tumorigenesis by precluding OIS. After undergoing an oncogene mutation, such as within BRAF^V600E, normal melanocytes undergo aberrant, but limited, proliferation and finally enter into senescence. These benign tumor cells form the so-called melanocytic nevus and often exhibit normal levels of ATG5 and autophagy. However, if ATG5 and, hence, autophagy are downregulated by, for example, promoter methylation, melanocytes bypass senescence, thereby undergoing accelerated proliferation and malignant transformation. These cancer cells with reduced levels of ATG5 and autophagy further evolve into melanoma.