Down-regulation of autophagy-related protein 5 (ATG5) contributes to the pathogenesis of early-stage cutaneous melanoma

The role of autophagy in cancer is controversial: Both tumor-suppressing and tumor-promoting functions have been reported. We show that a key regulator of autophagy, autophagy-related protein 5 (ATG5), is often down-regulated in primary melanomas compared to benign nevi, leading to a reduction of ba...

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Bibliographic Details
Published in:Science translational medicine 2013-09, Vol.5 (202), p.202ra123-202ra123
Main Authors: Liu, He, He, Zhaoyue, von Rütte, Thomas, Yousefi, Shida, Hunger, Robert E, Simon, Hans-Uwe
Format: Article
Language:English
Subjects:
Autophagy - genetics
Autophagy-Related Protein 5
Cell Line, Tumor
Cell Proliferation
Cellular Senescence - genetics
DNA Methylation - genetics
Down-Regulation - genetics
Gene Expression Regulation, Neoplastic
Gene Transfer Techniques
Humans
Melanocytes - metabolism
Melanocytes - pathology
Melanoma - genetics
Melanoma - pathology
Melanoma, Cutaneous Malignant
Microtubule-Associated Proteins - genetics
Models, Biological
Neoplasm Staging
Nevus, Pigmented - genetics
Nevus, Pigmented - pathology
Oncogenes - genetics
Promoter Regions, Genetic - genetics
Skin Neoplasms - genetics
Skin Neoplasms - pathology
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Summary:The role of autophagy in cancer is controversial: Both tumor-suppressing and tumor-promoting functions have been reported. We show that a key regulator of autophagy, autophagy-related protein 5 (ATG5), is often down-regulated in primary melanomas compared to benign nevi, leading to a reduction of basal autophagy as evidenced by a reduced expression of LC3. A follow-up of 158 primary melanoma patients showed that patients with low levels of ATG5 in their tumors had a reduced progression-free survival. In an in vitro model of melanoma tumorigenesis, where the BRAF oncogene was transduced into normal melanocytes, we observed that lowering ATG5 expression promoted proliferation by precluding oncogene-induced senescence. Hence, it appears that down-regulation of ATG5 contributes to tumorigenesis in early-stage cutaneous melanoma, and the expression of ATG5 and LC3 correlates with melanoma diagnosis and prognosis.
ISSN:1946-6234
1946-6242
DOI:10.1126/scitranslmed.3005864