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.

Specific c-Jun target genes in malignant melanoma

“…The enrichment of DNA fragments displayed as peaks in the promoter/enhancer regions of specific target genes (ENCODE) were localized to the promoter/enhancer regions of FosB, NFATC2, WEE1, PVR, MAP1LC3B and LGALS3 [17][18][19][20][21][22] ( Fig. 2, Table 2).…”

The impact of autophagy on the development of senescence in primary tubular epithelial cells

“…14 Based on the finding that stress-induced autophagy is often followed by the occurrence of senescent cells it was concluded that autophagy might act as a pro-senescent trigger. [15][16][17][18][19] Along these lines, Young et al first proposed autophagy as an effector mechanism for establishment of oncogenic senescence. 17 Autophagy was later also found to contribute to senescence of bile duct epithelial cells and progression toward primary biliary cirrhosis.…”

The MITF family of transcription factors: Role in endolysosomal biogenesis, Wnt signaling, and oncogenesis

“…Lysosomal and autophagosomal function is critical for the maintenance of proteostasis and for the ability of cells to respond to stress [77,80,81,87]. Although autophagy has been described as a tumor suppressing mechanism (given that loss of ATG genes promote cancer, including lymphomas and lung and liver carcinomas [88][89][90]), CQ and hydroxychloroquine (HCQ) (FDA-approved drugs for the prophylactic treatment of malaria, lupus erythematosus and rheumatoid arthritis) have never been linked to malignant transformation.…”

“…Interestingly, high MITF expression levels correlate with very low ATG5 and ATG7 levels in microarray expression data from a panel of 83 melanoma cell lines (appearing at positions 11,730 and 12,676, respectively, in Supplementary Table 1, p < 0.001). Macroautophagy contributes to the induction of oncogene-induced cell senescence, and melanomas with impaired autophagy and reduced ATG5 levels may escape this homeostatic mechanism [79][80][81]. High levels of MITF, which correlate with low levels of ATG5, might contribute to proliferation by inhibiting oncogene-induced senescence [82,83].…”