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Research Article
Cancer

Down-Regulation of Autophagy-Related Protein 5 (ATG5) Contributes to the Pathogenesis of Early-Stage Cutaneous Melanoma

Science Translational Medicine
11 Sep 2013
Vol 5, Issue 202
p. 202ra123

Getting Melanoma to Eat Itself

Autophagy, which literally means “self-eating,” is a normal cellular process that allows cells to get rid of unnecessary debris and may help them survive under conditions of stress. Autophagy is thought to be dysregulated in tumor cells, but its exact role is controversial because it appears to be beneficial under some conditions and harmful in others. Now, Liu and colleagues have tried to address this question by examining the role of autophagy in melanoma.
The authors specifically focused on one regulator of autophagy, called autophagy-related protein 5 (ATG5). In a group of almost 200 patients with melanoma and 150 with benign melanocytic nevi, the authors saw decreased expression and increased methylation of ATG5 in the tumors compared to benign nevi and normal skin cells. Moreover, the extent of ATG5 expression in patients’ melanoma samples correlated with progression-free survival, such that patients with more ATG5 in their tumors had a better prognosis. Similarly, up-regulating ATG5 in cultured tumor cells inhibited their proliferation and caused them to undergo senescence.
The role of ATG5 in melanoma patients’ survival needs to be validated in additional human studies, and similar research should be performed for other types of cancer. Thus far, it can only serve as a prognostic marker, but future research may uncover ways to treat melanoma and other cancers by forcing the tumors to produce more ATG5 and literally eat themselves.

Abstract

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.

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Supplementary Material

Summary

Fig. S1. ATG5 mRNA expression is compared among different cancer cell lines.
Fig. S2. ATG5 is homogeneously expressed in most of the patients.
Fig. S3. ATG5 expression is quantified in melanoma patients according to their Clark levels.
Fig. S4. The expression of ATG5, Beclin 1, LC3, and p62 is detected in melanoma and nevus patients.
Fig. S5. ATG5 expression and autophagy are down-regulated in a subpopulation of melanoma cell lines.
Fig. S6. A putative CpG island in the ATG5 promoter is illustrated using the online analysis tool EMBL-EBI CpG plot.
Fig. S7. Starvation-induced autophagic flux is shown in ATG5-deficient A-2058 melanoma cells in the presence and absence of 5-aza-dC.
Fig. S8. Autophagosome formation is shown by LC3 and Autodot staining.
Fig. S9. Overexpression of ATG5 induces apoptosis in melanoma cells.
Fig. S10. Treatment of ATG5-deficient melanoma cells with 5-aza-dC inhibits proliferation and induces senescence.
Fig. S11. Successful gene transfer in isolated melanocytes is demonstrated by immunoblotting.
Fig. S12. Knockdown of ATG5 increases proliferation of melanocytes expressing BRAF or HRAS oncogenes.
Fig. S13. Knockdown of ATG5 decreases autophagy in melanocytes expressing BRAF or HRAS oncogenes.
Fig. S14. Knockdown of ATG5 decreases senescence in melanocytes expressing BRAF or HRAS oncogenes.
Table S1. Information about the patients included in this study.
Table S2. Information about the patients selected for LC3 immunostaining analysis.
Table S3. ATG5 promoter methylation and ATG5 mRNA expression in melanoma cell lines.

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REFERENCES AND NOTES

1
Jemal A., Saraiya M., Patel P., Cherala S. S., Barnholtz-Sloan J., Kim J., Wiggins C. L., Wingo P. A., Recent trends in cutaneous melanoma incidence and death rates in the United States, 1992-2006. J. Am. Acad. Dermatol. 65 (Suppl. 1), S17–S25 (2011).
2
Davies H., Bignell G. R., Cox C., Stephens P., Edkins S., Clegg S., Teague J., Woffendin H., Garnett M. J., Bottomley W., Davis N., Dicks E., Ewing R., Floyd Y., Gray K., Hall S., Hawes R., Hughes J., Kosmidou V., Menzies A., Mould C., Parker A., Stevens C., Watt S., Hooper S., Wilson R., Jayatilake H., Gusterson B. A., Cooper C., Shipley J., Hargrave D., Pritchard-Jones K., Maitland N., Chenevix-Trench G., Riggins G. J., Bigner D. D., Palmieri G., Cossu A., Flanagan A., Nicholson A., Ho J. W., Leung S. Y., Yuen S. T., Weber B. L., Seigler H. F., Darrow T. L., Paterson H., Marais R., Marshall C. J., Wooster R., Stratton M. R., Futreal P. A., Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002).
3
Fecher L. A., Amaravadi R. K., Flaherty K. T., The MAPK pathway in melanoma. Curr. Opin. Oncol. 20, 183–189 (2008).
4
Stahl J. M., Sharma A., Cheung M., Zimmerman M., Cheng J. Q., Bosenberg M. W., Kester M., Sandirasegarane L., Robertson G. P., Deregulated Akt3 activity promotes development of malignant melanoma. Cancer Res. 64, 7002–7010 (2004).
5
Mizushima N., Komatsu M., Autophagy: Renovation of cells and tissues. Cell 147, 728–741 (2011).
6
Mizushima N., Levine B., Autophagy in mammalian development and differentiation. Nat. Cell Biol. 12, 823–830 (2010).
7
Rubinsztein D. C., Mariño G., Kroemer G., Autophagy and aging. Cell 146, 682–695 (2011).
8
Levine B., Mizushima N., Virgin H. W., Autophagy in immunity and inflammation. Nature 469, 323–335 (2011).
9
White E., Deconvoluting the context-dependent role for autophagy in cancer. Nat. Rev. Cancer 12, 401–410 (2012).
10
Levine B., Klionsky D. J., Development by self-digestion: Molecular mechanisms and biological functions of autophagy. Dev. Cell 6, 463–477 (2004).
11
Qu X., Yu J., Bhagat G., Furuya N., Hibshoosh H., Troxel A., Rosen J., Eskelinen E. L., Mizushima N., Ohsumi Y., Cattoretti G., Levine B., Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Invest. 112, 1809–1820 (2003).
12
Liang X. H., Jackson S., Seaman M., Brown K., Kempkes B., Hibshoosh H., Levine B., Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402, 672–676 (1999).
13
Wang R. C., Wei Y., An Z., Zou Z., Xiao G., Bhagat G., White M., Reichelt J., Levine B., Akt-mediated regulation of autophagy and tumorigenesis through Beclin 1 phosphorylation. Science 338, 956–959 (2012).
14
Liang C., Feng P., Ku B., Dotan I., Canaani D., Oh B. H., Jung J. U., Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat. Cell Biol. 8, 688–699 (2006).
15
Debnath J., Mills K. R., Collins N. L., Reginato M. J., Muthuswamy S. K., Brugge J. S., The role of apoptosis in creating and maintaining luminal space within normal and oncogene-expressing mammary acini. Cell 111, 29–40 (2002).
16
Fung C., Lock R., Gao S., Salas E., Debnath J., Induction of autophagy during extracellular matrix detachment promotes cell survival. Mol. Biol. Cell 19, 797–806 (2008).
17
Lock R., Debnath J., Extracellular matrix regulation of autophagy. Curr. Opin. Cell Biol. 20, 583–588 (2008).
18
Han C., Sun B., Wang W., Cai W., Lou D., Sun Y., Zhao X., Overexpression of microtubule-associated protein-1 light chain 3 is associated with melanoma metastasis and vasculogenic mimicry. Tohoku J. Exp. Med. 223, 243–251 (2011).
19
Hara Y., Nakamura M., Overexpression of autophagy-related beclin-1 in advanced malignant melanoma and its low expression in melanoma-in-situ. Eur. J. Dermatol. 22, 128–129 (2012).
20
Kon M., Kiffin R., Koga H., Chapochnick J., Macian F., Varticovski L., Cuervo A. M., Chaperone-mediated autophagy is required for tumor growth. Sci. Transl. Med. 3, 109ra117 (2011).
21
Yousefi S., Perozzo R., Schmid I., Ziemiecki A., Schaffner T., Scapozza L., Brunner T., Simon H. U., Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat. Cell Biol. 8, 1124–1132 (2006).
22
Klionsky D. J., Abdalla F. C., Abeliovich H., Abraham R. T., Acevedo-Arozena A., Adeli K., Agholme L., Agnello M., Agostinis P., Aguirre-Ghiso J. A., Ahn H. J., Ait-Mohamed O., Ait-Si-Ali S., Akematsu T., Akira S., Al-Younes H. M., Al-Zeer M. A., Albert M. L., Albin R. L., Alegre-Abarrategui J., Aleo M. F., Alirezaei M., Almasan A., Almonte-Becerril M., Amano A., Amaravadi R., Amarnath S., Amer A. O., Andrieu-Abadie N., Anantharam V., Ann D. K., Anoopkumar-Dukie S., Aoki H., Apostolova N., Arancia G., Aris J. P., Asanuma K., Asare N. Y., Ashida H., Askanas V., Askew D. S., Auberger P., Baba M., Backues S. K., Baehrecke E. H., Bahr B. A., Bai X. Y., Bailly Y., Baiocchi R., Baldini G., Balduini W., Ballabio A., Bamber B. A., Bampton E. T., Bánhegyi G., Bartholomew C. R., Bassham D. C., Bast R. C., Batoko H., Bay B. H., Beau I., Béchet D. M., Begley T. J., Behl C., Behrends C., Bekri S., Bellaire B., Bendall L. J., Benetti L., Berliocchi L., Bernardi H., Bernassola F., Besteiro S., Bhatia-Kissova I., Bi X., Biard-Piechaczyk M., Blum J. S., Boise L. H., Bonaldo P., Boone D. L., Bornhauser B. C., Bortoluci K. R., Bossis I., Bost F., Bourquin J. P., Boya P., Boyer-Guittaut M., Bozhkov P. V., Brady N. R., Brancolini C., Brech A., Brenman J. E., Brennand A., Bresnick E. H., Brest P., Bridges D., Bristol M. L., Brookes P. S., Brown E. J., Brumell J. H., Brunetti-Pierri N., Brunk U. T., Bulman D. E., Bultman S. J., Bultynck G., Burbulla L. F., Bursch W., Butchar J. P., Buzgariu W., Bydlowski S. P., Cadwell K., Cahová M., Cai D., Cai J., Cai Q., Calabretta B., Calvo-Garrido J., Camougrand N., Campanella M., Campos-Salinas J., Candi E., Cao L., Caplan A. B., Carding S. R., Cardoso S. M., Carew J. S., Carlin C. R., Carmignac V., Carneiro L. A., Carra S., Caruso R. A., Casari G., Casas C., Castino R., Cebollero E., Cecconi F., Celli J., Chaachouay H., Chae H. J., Chai C. Y., Chan D. C., Chan E. Y., Chang R. C., Che C. M., Chen C. C., Chen G. C., Chen G. Q., Chen M., Chen Q., Chen S. S., Chen W., Chen X., Chen X., Chen X., Chen Y. G., Chen Y., Chen Y., Chen Y. J., Chen Z., Cheng A., Cheng C. H., Cheng Y., Cheong H., Cheong J. H., Cherry S., Chess-Williams R., Cheung Z. H., Chevet E., Chiang H. L., Chiarelli R., Chiba T., Chin L. S., Chiou S. H., Chisari F. V., Cho C. H., Cho D. H., Choi A. M., Choi D., Choi K. S., Choi M. E., Chouaib S., Choubey D., Choubey V., Chu C. T., Chuang T. H., Chueh S. H., Chun T., Chwae Y. J., Chye M. L., Ciarcia R., Ciriolo M. R., Clague M. J., Clark R. S., Clarke P. G., Clarke R., Codogno P., Coller H. A., Colombo M. I., Comincini S., Condello M., Condorelli F., Cookson M. R., Coombs G. H., Coppens I., Corbalan R., Cossart P., Costelli P., Costes S., Coto-Montes A., Couve E., Coxon F. P., Cregg J. M., Crespo J. L., Cronjé M. J., Cuervo A. M., Cullen J. J., Czaja M. J., D’Amelio M., Darfeuille-Michaud A., Davids L. M., Davies F. E., De Felici M., de Groot J. F., de Haan C. A., De Martino L., De Milito A., De Tata V., Debnath J., Degterev A., Dehay B., Delbridge L. M., Demarchi F., Deng Y. Z., Dengjel J., Dent P., Denton D., Deretic V., Desai S. D., Devenish R. J., Di Gioacchino M., Di Paolo G., Di Pietro C., Díaz-Araya G., Díaz-Laviada I., Diaz-Meco M. T., Diaz-Nido J., Dikic I., Dinesh-Kumar S. P., Ding W. X., Distelhorst C. W., Diwan A., Djavaheri-Mergny M., Dokudovskaya S., Dong Z., Dorsey F. C., Dosenko V., Dowling J. J., Doxsey S., Dreux M., Drew M. E., Duan Q., Duchosal M. A., Duff K., Dugail I., Durbeej M., Duszenko M., Edelstein C. L., Edinger A. L., Egea G., Eichinger L., Eissa N. T., Ekmekcioglu S., El-Deiry W. S., Elazar Z., Elgendy M., Ellerby L. M., Eng K. E., Engelbrecht A. M., Engelender S., Erenpreisa J., Escalante R., Esclatine A., Eskelinen E. L., Espert L., Espina V., Fan H., Fan J., Fan Q. W., Fan Z., Fang S., Fang Y., Fanto M., Fanzani A., Farkas T., Farré J. C., Faure M., Fechheimer M., Feng C. G., Feng J., Feng Q., Feng Y., Fésüs L., Feuer R., Figueiredo-Pereira M. E., Fimia G. M., Fingar D. C., Finkbeiner S., Finkel T., Finley K. D., Fiorito F., Fisher E. A., Fisher P. B., Flajolet M., Florez-McClure M. L., Florio S., Fon E. A., Fornai F., Fortunato F., Fotedar R., Fowler D. H., Fox H. S., Franco R., Frankel L. B., Fransen M., Fuentes J. M., Fueyo J., Fujii J., Fujisaki K., Fujita E., Fukuda M., Furukawa R. H., Gaestel M., Gailly P., Gajewska M., Galliot B., Galy V., Ganesh S., Ganetzky B., Ganley I. G., Gao F. B., Gao G. F., Gao J., Garcia L., Garcia-Manero G., Garcia-Marcos M., Garmyn M., Gartel A. L., Gatti E., Gautel M., Gawriluk T. R., Gegg M. E., Geng J., Germain M., Gestwicki J. E., Gewirtz D. A., Ghavami S., Ghosh P., Giammarioli A. M., Giatromanolaki A. N., Gibson S. B., Gilkerson R. W., Ginger M. L., Ginsberg H. N., Golab J., Goligorsky M. S., Golstein P., Gomez-Manzano C., Goncu E., Gongora C., Gonzalez C. D., Gonzalez R., González-Estévez C., González-Polo R. A., Gonzalez-Rey E., Gorbunov N. V., Gorski S., Goruppi S., Gottlieb R. A., Gozuacik D., Granato G. E., Grant G. D., Green K. N., Gregorc A., Gros F., Grose C., Grunt T. W., Gual P., Guan J. L., Guan K. L., Guichard S. M., Gukovskaya A. S., Gukovsky I., Gunst J., Gustafsson A. B., Halayko A. J., Hale A. N., Halonen S. K., Hamasaki M., Han F., Han T., Hancock M. K., Hansen M., Harada H., Harada M., Hardt S. E., Harper J. W., Harris A. L., Harris J., Harris S. D., Hashimoto M., Haspel J. A., Hayashi S., Hazelhurst L. A., He C., He Y. W., Hébert M. J., Heidenreich K. A., Helfrich M. H., Helgason G. V., Henske E. P., Herman B., Herman P. K., Hetz C., Hilfiker S., Hill J. A., Hocking L. J., Hofman P., Hofmann T. G., Höhfeld J., Holyoake T. L., Hong M. H., Hood D. A., Hotamisligil G. S., Houwerzijl E. J., Høyer-Hansen M., Hu B., Hu C. A., Hu H. M., Hua Y., Huang C., Huang J., Huang S., Huang W. P., Huber T. B., Huh W. K., Hung T. H., Hupp T. R., Hur G. M., Hurley J. B., Hussain S. N., Hussey P. J., Hwang J. J., Hwang S., Ichihara A., Ilkhanizadeh S., Inoki K., Into T., Iovane V., Iovanna J. L., Ip N. Y., Isaka Y., Ishida H., Isidoro C., Isobe K., Iwasaki A., Izquierdo M., Izumi Y., Jaakkola P. M., Jäättelä M., Jackson G. R., Jackson W. T., Janji B., Jendrach M., Jeon J. H., Jeung E. B., Jiang H., Jiang H., Jiang J. X., Jiang M., Jiang Q., Jiang X., Jiang X., Jiménez A., Jin M., Jin S., Joe C. O., Johansen T., Johnson D. E., Johnson G. V., Jones N. L., Joseph B., Joseph S. K., Joubert A. M., Juhász G., Juillerat-Jeanneret L., Jung C. H., Jung Y. K., Kaarniranta K., Kaasik A., Kabuta T., Kadowaki M., Kagedal K., Kamada Y., Kaminskyy V. O., Kampinga H. H., Kanamori H., Kang C., Kang K. B., Kang K. I., Kang R., Kang Y. A., Kanki T., Kanneganti T. D., Kanno H., Kanthasamy A. G., Kanthasamy A., Karantza V., Kaushal G. P., Kaushik S., Kawazoe Y., Ke P. Y., Kehrl J. H., Kelekar A., Kerkhoff C., Kessel D. H., Khalil H., Kiel J. A., Kiger A. A., Kihara A., Kim D. R., Kim D. H., Kim D. H., Kim E. K., Kim H. R., Kim J. S., Kim J. H., Kim J. C., Kim J. K., Kim P. K., Kim S. W., Kim Y. S., Kim Y., Kimchi A., Kimmelman A. C., King J. S., Kinsella T. J., Kirkin V., Kirshenbaum L. A., Kitamoto K., Kitazato K., Klein L., Klimecki W. T., Klucken J., Knecht E., Ko B. C., Koch J. C., Koga H., Koh J. Y., Koh Y. H., Koike M., Komatsu M., Kominami E., Kong H. J., Kong W. J., Korolchuk V. I., Kotake Y., Koukourakis M. I., Kouri Flores J. B., Kovács A. L., Kraft C., Krainc D., Krämer H., Kretz-Remy C., Krichevsky A. M., Kroemer G., Krüger R., Krut O., Ktistakis N. T., Kuan C. Y., Kucharczyk R., Kumar A., Kumar R., Kumar S., Kundu M., Kung H. J., Kurz T., Kwon H. J., La Spada A. R., Lafont F., Lamark T., Landry J., Lane J. D., Lapaquette P., Laporte J. F., László L., Lavandero S., Lavoie J. N., Layfield R., Lazo P. A., Le W., Le Cam L., Ledbetter D. J., Lee A. J., Lee B. W., Lee G. M., Lee J., Lee J. H., Lee M., Lee M. S., Lee S. H., Leeuwenburgh C., Legembre P., Legouis R., Lehmann M., Lei H. Y., Lei Q. Y., Leib D. A., Leiro J., Lemasters J. J., Lemoine A., Lesniak M. S., Lev D., Levenson V. V., Levine B., Levy E., Li F., Li J. L., Li L., Li S., Li W., Li X. J., Li Y. B., Li Y. P., Liang C., Liang Q., Liao Y. F., Liberski P. P., Lieberman A., Lim H. J., Lim K. L., Lim K., Lin C. F., Lin F. C., Lin J., Lin J. D., Lin K., Lin W. W., Lin W. C., Lin Y. L., Linden R., Lingor P., Lippincott-Schwartz J., Lisanti M. P., Liton P. B., Liu B., Liu C. F., Liu K., Liu L., Liu Q. A., Liu W., Liu Y. C., Liu Y., Lockshin R. A., Lok C. N., Lonial S., Loos B., Lopez-Berestein G., López-Otín C., Lossi L., Lotze M. T., Lőw P., Lu B., Lu B., Lu B., Lu Z., Luciano F., Lukacs N. W., Lund A. H., Lynch-Day M. A., Ma Y., Macian F., MacKeigan J. P., Macleod K. F., Madeo F., Maiuri L., Maiuri M. C., Malagoli D., Malicdan M. C., Malorni W., Man N., Mandelkow E. M., Manon S., Manov I., Mao K., Mao X., Mao Z., Marambaud P., Marazziti D., Marcel Y. L., Marchbank K., Marchetti P., Marciniak S. J., Marcondes M., Mardi M., Marfe G., Mariño G., Markaki M., Marten M. R., Martin S. J., Martinand-Mari C., Martinet W., Martinez-Vicente M., Masini M., Matarrese P., Matsuo S., Matteoni R., Mayer A., Mazure N. M., McConkey D. J., McConnell M. J., McDermott C., McDonald C., McInerney G. M., McKenna S. L., McLaughlin B., McLean P. J., McMaster C. R., McQuibban G. A., Meijer A. J., Meisler M. H., Meléndez A., Melia T. J., Melino G., Mena M. A., Menendez J. A., Menna-Barreto R. F., Menon M. B., Menzies F. M., Mercer C. A., Merighi A., Merry D. E., Meschini S., Meyer C. G., Meyer T. F., Miao C. Y., Miao J. Y., Michels P. A., Michiels C., Mijaljica D., Milojkovic A., Minucci S., Miracco C., Miranti C. K., Mitroulis I., Miyazawa K., Mizushima N., Mograbi B., Mohseni S., Molero X., Mollereau B., Mollinedo F., Momoi T., Monastyrska I., Monick M. M., Monteiro M. J., Moore M. N., Mora R., Moreau K., Moreira P. I., Moriyasu Y., Moscat J., Mostowy S., Mottram J. C., Motyl T., Moussa C. E., Müller S., Muller S., Münger K., Münz C., Murphy L. O., Murphy M. E., Musarò A., Mysorekar I., Nagata E., Nagata K., Nahimana A., Nair U., Nakagawa T., Nakahira K., Nakano H., Nakatogawa H., Nanjundan M., Naqvi N. I., Narendra D. P., Narita M., Navarro M., Nawrocki S. T., Nazarko T. Y., Nemchenko A., Netea M. G., Neufeld T. P., Ney P. A., Nezis I. P., Nguyen H. P., Nie D., Nishino I., Nislow C., Nixon R. A., Noda T., Noegel A. A., Nogalska A., Noguchi S., Notterpek L., Novak I., Nozaki T., Nukina N., Nürnberger T., Nyfeler B., Obara K., Oberley T. D., Oddo S., Ogawa M., Ohashi T., Okamoto K., Oleinick N. L., Oliver F. J., Olsen L. J., Olsson S., Opota O., Osborne T. F., Ostrander G. K., Otsu K., Ou J. H., Ouimet M., Overholtzer M., Ozpolat B., Paganetti P., Pagnini U., Pallet N., Palmer G. E., Palumbo C., Pan T., Panaretakis T., Pandey U. B., Papackova Z., Papassideri I., Paris I., Park J., Park O. K., Parys J. B., Parzych K. R., Patschan S., Patterson C., Pattingre S., Pawelek J. M., Peng J., Perlmutter D. H., Perrotta I., Perry G., Pervaiz S., Peter M., Peters G. J., Petersen M., Petrovski G., Phang J. M., Piacentini M., Pierre P., Pierrefite-Carle V., Pierron G., Pinkas-Kramarski R., Piras A., Piri N., Platanias L. C., Pöggeler S., Poirot M., Poletti A., Poüs C., Pozuelo-Rubio M., Prætorius-Ibba M., Prasad A., Prescott M., Priault M., Produit-Zengaffinen N., Progulske-Fox A., Proikas-Cezanne T., Przedborski S., Przyklenk K., Puertollano R., Puyal J., Qian S. B., Qin L., Qin Z. H., Quaggin S. E., Raben N., Rabinowich H., Rabkin S. W., Rahman I., Rami A., Ramm G., Randall G., Randow F., Rao V. A., Rathmell J. C., Ravikumar B., Ray S. K., Reed B. H., Reed J. C., Reggiori F., Régnier-Vigouroux A., Reichert A. S., Reiners J. J., Reiter R. J., Ren J., Revuelta J. L., Rhodes C. J., Ritis K., Rizzo E., Robbins J., Roberge M., Roca H., Roccheri M. C., Rocchi S., Rodemann H. P., Rodríguez de Córdoba S., Rohrer B., Roninson I. B., Rosen K., Rost-Roszkowska M. M., Rouis M., Rouschop K. M., Rovetta F., Rubin B. P., Rubinsztein D. C., Ruckdeschel K., Rucker E. B., Rudich A., Rudolf E., Ruiz-Opazo N., Russo R., Rusten T. E., Ryan K. M., Ryter S. W., Sabatini D. M., Sadoshima J., Saha T., Saitoh T., Sakagami H., Sakai Y., Salekdeh G. H., Salomoni P., Salvaterra P. M., Salvesen G., Salvioli R., Sanchez A. M., Sánchez-Alcázar J. A., Sánchez-Prieto R., Sandri M., Sankar U., Sansanwal P., Santambrogio L., Saran S., Sarkar S., Sarwal M., Sasakawa C., Sasnauskiene A., Sass M., Sato K., Sato M., Schapira A. H., Scharl M., Schätzl H. M., Scheper W., Schiaffino S., Schneider C., Schneider M. E., Schneider-Stock R., Schoenlein P. V., Schorderet D. F., Schüller C., Schwartz G. K., Scorrano L., Sealy L., Seglen P. O., Segura-Aguilar J., Seiliez I., Seleverstov O., Sell C., Seo J. B., Separovic D., Setaluri V., Setoguchi T., Settembre C., Shacka J. J., Shanmugam M., Shapiro I. M., Shaulian E., Shaw R. J., Shelhamer J. H., Shen H. M., Shen W. C., Sheng Z. H., Shi Y., Shibuya K., Shidoji Y., Shieh J. J., Shih C. M., Shimada Y., Shimizu S., Shintani T., Shirihai O. S., Shore G. C., Sibirny A. A., Sidhu S. B., Sikorska B., Silva-Zacarin E. C., Simmons A., Simon A. K., Simon H. U., Simone C., Simonsen A., Sinclair D. A., Singh R., Sinha D., Sinicrope F. A., Sirko A., Siu P. M., Sivridis E., Skop V., Skulachev V. P., Slack R. S., Smaili S. S., Smith D. R., Soengas M. S., Soldati T., Song X., Sood A. K., Soong T. W., Sotgia F., Spector S. A., Spies C. D., Springer W., Srinivasula S. M., Stefanis L., Steffan J. S., Stendel R., Stenmark H., Stephanou A., Stern S. T., Sternberg C., Stork B., Strålfors P., Subauste C. S., Sui X., Sulzer D., Sun J., Sun S. Y., Sun Z. J., Sung J. J., Suzuki K., Suzuki T., Swanson M. S., Swanton C., Sweeney S. T., Sy L. K., Szabadkai G., Tabas I., Taegtmeyer H., Tafani M., Takács-Vellai K., Takano Y., Takegawa K., Takemura G., Takeshita F., Talbot N. J., Tan K. S., Tanaka K., Tanaka K., Tang D., Tang D., Tanida I., Tannous B. A., Tavernarakis N., Taylor G. S., Taylor G. A., Taylor J. P., Terada L. S., Terman A., Tettamanti G., Thevissen K., Thompson C. B., Thorburn A., Thumm M., Tian F., Tian Y., Tocchini-Valentini G., Tolkovsky A. M., Tomino Y., Tönges L., Tooze S. A., Tournier C., Tower J., Towns R., Trajkovic V., Travassos L. H., Tsai T. F., Tschan M. P., Tsubata T., Tsung A., Turk B., Turner L. S., Tyagi S. C., Uchiyama Y., Ueno T., Umekawa M., Umemiya-Shirafuji R., Unni V. K., Vaccaro M. I., Valente E. M., Van den Berghe G., van der Klei I. J., van Doorn W., van Dyk L. F., van Egmond M., van Grunsven L. A., Vandenabeele P., Vandenberghe W. P., Vanhorebeek I., Vaquero E. C., Velasco G., Vellai T., Vicencio J. M., Vierstra R. D., Vila M., Vindis C., Viola G., Viscomi M. T., Voitsekhovskaja O. V., von Haefen C., Votruba M., Wada K., Wade-Martins R., Walker C. L., Walsh C. M., Walter J., Wan X. B., Wang A., Wang C., Wang D., Wang F., Wang F., Wang G., Wang H., Wang H. G., Wang H. D., Wang J., Wang K., Wang M., Wang R. C., Wang X., Wang X., Wang Y. J., Wang Y., Wang Z., Wang Z. C., Wang Z., Wansink D. G., Ward D. M., Watada H., Waters S. L., Webster P., Wei L., Weihl C. C., Weiss W. A., Welford S. M., Wen L. P., Whitehouse C. A., Whitton J. L., Whitworth A. J., Wileman T., Wiley J. W., Wilkinson S., Willbold D., Williams R. L., Williamson P. R., Wouters B. G., Wu C., Wu D. C., Wu W. K., Wyttenbach A., Xavier R. J., Xi Z., Xia P., Xiao G., Xie Z., Xie Z., Xu D. Z., Xu J., Xu L., Xu X., Yamamoto A., Yamamoto A., Yamashina S., Yamashita M., Yan X., Yanagida M., Yang D. S., Yang E., Yang J. M., Yang S. Y., Yang W., Yang W. Y., Yang Z., Yao M. C., Yao T. P., Yeganeh B., Yen W. L., Yin J. J., Yin X. M., Yoo O. J., Yoon G., Yoon S. Y., Yorimitsu T., Yoshikawa Y., Yoshimori T., Yoshimoto K., You H. J., Youle R. J., Younes A., Yu L., Yu L., Yu S. W., Yu W. H., Yuan Z. M., Yue Z., Yun C. H., Yuzaki M., Zabirnyk O., Silva-Zacarin E., Zacks D., Zacksenhaus E., Zaffaroni N., Zakeri Z., Zeh H. J., Zeitlin S. O., Zhang H., Zhang H. L., Zhang J., Zhang J. P., Zhang L., Zhang L., Zhang M. Y., Zhang X. D., Zhao M., Zhao Y. F., Zhao Y., Zhao Z. J., Zheng X., Zhivotovsky B., Zhong Q., Zhou C. Z., Zhu C., Zhu W. G., Zhu X. F., Zhu X., Zhu Y., Zoladek T., Zong W. X., Zorzano A., Zschocke J., Zuckerbraun B., Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8, 445–544 (2012).
23
Beroukhim R., Mermel C. H., Porter D., Wei G., Raychaudhuri S., Donovan J., Barretina J., Boehm J. S., Dobson J., Urashima M., Mc Henry K. T., Pinchback R. M., Ligon A. H., Cho Y. J., Haery L., Greulich H., Reich M., Winckler W., Lawrence M. S., Weir B. A., Tanaka K. E., Chiang D. Y., Bass A. J., Loo A., Hoffman C., Prensner J., Liefeld T., Gao Q., Yecies D., Signoretti S., Maher E., Kaye F. J., Sasaki H., Tepper J. E., Fletcher J. A., Tabernero J., Baselga J., Tsao M. S., Demichelis F., Rubin M. A., Janne P. A., Daly M. J., Nucera C., Levine R. L., Ebert B. L., Gabriel S., Rustgi A. K., Antonescu C. R., Ladanyi M., Letai A., Garraway L. A., Loda M., Beer D. G., True L. D., Okamoto A., Pomeroy S. L., Singer S., Golub T. R., Lander E. S., Getz G., Sellers W. R., Meyerson M., The landscape of somatic copy-number alteration across human cancers. Nature 463, 899–905 (2010).
24
Rothhammer T., Bosserhoff A. K., Epigenetic events in malignant melanoma. Pigment Cell Res. 20, 92–111 (2007).
25
Soengas M. S., Capodieci P., Polsky D., Mora J., Esteller M., Opitz-Araya X., McCombie R., Herman J. G., Gerald W. L., Lazebnik Y. A., Cordón-Cardó C., Lowe S. W., Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature 409, 207–211 (2001).
26
Saxonov S., Berg P., Brutlag D. L., A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc. Natl. Acad. Sci. U.S.A. 103, 1412–1417 (2006).
27
Munafó D. B., Colombo M. I., A novel assay to study autophagy: Regulation of autophagosome vacuole size by amino acid deprivation. J. Cell Sci. 114, 3619–3629 (2001).
28
Bayreuther K., Rodemann H. P., Hommel R., Dittmann K., Albiez M., Francz P. I., Human skin fibroblasts in vitro differentiate along a terminal cell lineage. Proc. Natl. Acad. Sci. U.S.A. 85, 5112–5116 (1988).
29
Michaloglou C., Vredeveld L. C., Soengas M. S., Denoyelle C., Kuilman T., van der Horst C. M., Majoor D. M., Shay J. W., Mooi W. J., Peeper D. S., BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature 436, 720–724 (2005).
30
Pollock P. M., Harper U. L., Hansen K. S., Yudt L. M., Stark M., Robbins C. M., Moses T. Y., Hostetter G., Wagner U., Kakareka J., Salem G., Pohida T., Heenan P., Duray P., Kallioniemi O., Hayward N. K., Trent J. M., Meltzer P. S., High frequency of BRAF mutations in nevi. Nat. Genet. 33, 19–20 (2003).
31
Walker G. J., Soyer H. P., Terzian T., Box N. F., Modelling melanoma in mice. Pigment Cell Melanoma Res. 24, 1158–1176 (2011).
32
Platz A., Egyhazi S., Ringborg U., Hansson J., Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol. Oncol. 4, 395–405 (2008).
33
Takamura A., Komatsu M., Hara T., Sakamoto A., Kishi C., Waguri S., Eishi Y., Hino O., Tanaka K., Mizushima N., Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 25, 795–800 (2011).
34
Ma X. H., Piao S., Wang D., McAfee Q. W., Nathanson K. L., Lum J. J., Li L. Z., Amaravadi R. K., Measurements of tumor cell autophagy predict invasiveness, resistance to chemotherapy, and survival in melanoma. Clin. Cancer Res. 17, 3478–3489 (2011).
35
Marino M. L., Pellegrini P., Di Lernia G., Djavaheri-Mergny M., Brnjic S., Zhang X., Hägg M., Linder S., Fais S., Codogno P., De Milito A., Autophagy is a protective mechanism for human melanoma cells under acidic stress. J. Biol. Chem. 287, 30664–30676 (2012).
36
Degenhardt K., Mathew R., Beaudoin B., Bray K., Anderson D., Chen G., Mukherjee C., Shi Y., Gélinas C., Fan Y., Nelson D. A., Jin S., White E., Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10, 51–64 (2006).
37
Miracco C., Cevenini G., Franchi A., Luzi P., Cosci E., Mourmouras V., Monciatti I., Mannucci S., Biagioli M., Toscano M., Moretti D., Lio R., Massi D., Beclin 1 and LC3 autophagic gene expression in cutaneous melanocytic lesions. Hum. Pathol. 41, 503–512 (2010).
38
Sinnberg T., Lasithiotakis K., Niessner H., Schittek B., Flaherty K. T., Kulms D., Maczey E., Campos M., Gogel J., Garbe C., Meier F., Inhibition of PI3K-AKT-mTOR signaling sensitizes melanoma cells to cisplatin and temozolomide. J. Invest. Dermatol. 129, 1500–1515 (2009).
39
Salaun B., Lebecque S., Matikainen S., Rimoldi D., Romero P., Toll-like receptor 3 expressed by melanoma cells as a target for therapy? Clin. Cancer Res. 13, 4565–4574 (2007).
40
Wilhelm M., Collier I., Kronberger A., Eisen A., Marmer B., Grant G., Bauer E., Goldberg G., Human skin fibroblast stromelysin: Structure, glycosylation, substrate specificity, and differential expression in normal and tumorigenic cells. Proc. Natl. Acad. Sci. U.S.A. 84, 6725–6729 (1987).
41
Zeise E., Weichenthal M., Schwarz T., Kulms D., Resistance of human melanoma cells against the death ligand TRAIL is reversed by ultraviolet-B radiation via downregulation of FLIP. J. Invest. Dermatol. 123, 746–754 (2004).
42
Rodriguez J., Yáñez J., Vicente V., Alcaraz M., Benavente-García O., Castillo J., Lorente J., Lozano J. A., Effects of several flavonoids on the growth of B16F10 and SK-MEL-1 melanoma cell lines: Relationship between structure and activity. Melanoma Res. 12, 99–107 (2002).
43
Mannal P. W., Schneider J., Tangada A., McDonald D., McFadden D. W., Honokiol produces anti-neoplastic effects on melanoma cells in vitro. J. Surg. Oncol. 104, 260–264 (2011).
44
Young A. R., Narita M., Ferreira M., Kirschner K., Sadaie M., Darot J. F., Tavaré S., Arakawa S., Shimizu S., Watt F. M., Narita M., Autophagy mediates the mitotic senescence transition. Genes Dev. 23, 798–803 (2009).
45
Okayama H., Chen C., Calcium phosphate mediated gene transfer into established cell lines. Methods Mol. Biol. 7, 15–21 (1991).

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Published In

Science Translational Medicine
Volume 5 | Issue 202
September 2013

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Received: 4 February 2013
Accepted: 6 August 2013

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Acknowledgments

We thank F. Jakob and N. Germic (both at the Institute of Pharmacology, University of Bern) for excellent technical assistance. Funding: Supported by the Swiss National Science Foundation and Swiss Cancer League. Author contributions: H.L., R.E.H., and H.-U.S. devised the experiments. R.E.H. recruited and characterized the cohort of patients and provided tissue samples. H.L. performed all experiments, with the exception of the following: T.v.R. and S.Y. performed ATG5 immunofluorescence analysis, and Z.H. helped with lentiviral gene transfer experiments, isolated normal human melanocytes, and performed the quantitative analysis after immunohistological staining and statistical analysis. H.L. and H.-U.S. wrote the manuscript. Competing interests: The authors declare that they have no competing interests.

Authors

Affiliations

He Liu
Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.
Zhaoyue He
Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.
Thomas von Rütte
Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.
Shida Yousefi
Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.
Robert E. Hunger
Department of Dermatology, Inselspital, University Hospital Bern, CH-3010 Bern, Switzerland.
Hans-Uwe Simon* [email protected]
Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.

Notes

*
Corresponding author. E-mail: [email protected]

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