Abstract

Evolutionarily conserved across eukaryotic cells, macroautophagy (herein autophagy) is an intracellular catabolic degradative process targeting damaged and superfluous cellular proteins, organelles, and other cytoplasmic components. Mechanistically, it involves formation of double-membrane vesicles called autophagosomes that capture cytosolic cargo and deliver it to lysosomes, wherein the breakdown products are eventually recycled back to the cytoplasm. Dysregulation of autophagy often results in various disease manifestations, including neurodegeneration, microbial infections, and cancer. In the case of cancer, extensive attention has been devoted to understanding the paradoxical roles of autophagy in tumor suppression and tumor promotion. In this review, while we summarize how this self-eating process is implicated at various stages of tumorigenesis, most importantly, we address the link between autophagy and hallmarks of cancer. This would eventually provide a better understanding of tumor dependence on autophagy. We also discuss how therapeutics targeting autophagy can counter various transformations involved in tumorigenesis. Finally, this review will provide a novel insight into the mutational landscapes of autophagy-related genes in several human cancers, using genetic information collected from an array of cancers.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1

    Mizushima N. Autophagy: process and function. Genes Dev. 2007;21:2861–73.

  2. 2

    Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140:313–26.

  3. 3

    Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E, et al. Cloning and genomic organization of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics. 1999;59:59–65.

  4. 4

    Ameisen JC. On the origin, evolution, and nature of programmed cell death: a timeline of four billion years. Cell Death Differ. 2002;9:367–93.

  5. 5

    Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010;221:3–12.

  6. 6

    Nixon RA. The role of autophagy in neurodegenerative disease. Nat Med. 2013;19:983–97.

  7. 7

    Son JH, Shim JH, Kim K-H, Ha J-Y, Han JY. Neuronal autophagy and neurodegenerative diseases. Exp Mol Med. 2012;44:89–98.

  8. 8

    Rabinowitz JD, White E. Autophagy and metabolism. Science. 2010;330:1344–8.

  9. 9

    Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, et al. Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. Genes Dev. 2007;21:1621–35.

  10. 10

    Bellot G, Garcia-Medina R, Gounon P, Chiche J, Roux D, Pouysségur J, et al. Hypoxia-induced autophagy is mediated through hypoxia-inducible factor induction of BNIP3 and BNIP3L via their BH3 domains. Mol Cell Biol. 2009;29:2570–81.

  11. 11

    Bauckman KA, Owusu-Boaitey N, Mysorekar IU. Selective autophagy: xenophagy. Methods. 2015;75:120–7.

  12. 12

    Chandra P, Kumar D. Selective autophagy gets more selective: uncoupling of autophagy flux and xenophagy flux in Mycobacterium tuberculosis-infected macrophages. Autophagy. 2016;12:608–9.

  13. 13

    Levine B. Eating oneself and uninvited guests: autophagy-related pathways in cellular defense. Cell. 2005;120:159–62.

  14. 14

    B’Chir W, Maurin AC, Carraro V, Averous J, Jousse C, Muranishi Y, et al. The eIF2alpha/ATF4 pathway is essential for stress-induced autophagy gene expression. Nucleic Acids Res. 2013;41:7683–99.

  15. 15

    Son Y, Cheong YK, Kim NH, Chung HT, Kang DG, Pae HO. Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways?J Signal Transduct. 2011;2011:792639.

  16. 16

    Oberstein A, Jeffrey PD, Shi Y. Crystal structure of the Bcl-XL-Beclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem. 2007;282:13123–32.

  17. 17

    Liang XH, Kleeman LK, Jiang HH, Gordon G, Goldman JE, Berry G, et al. Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J Virol. 1998;72:8586–96.

  18. 18

    Filomeni G, De Zio D, Cecconi F. Oxidative stress and autophagy: the clash between damage and metabolic needs. Cell Death Differ. 2015;22:377–88.

  19. 19

    Kroemer G, Mariño G, Levine B. Autophagy and the integrated stress response. Mol Cell. 2010;40:280–93.

  20. 20

    Dibble CC, Manning BD. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol. 2013;15:555–64.

  21. 21

    Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13:132–41.

  22. 22

    Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol. 2002;4:648–57.

  23. 23

    Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM. Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell. 2010;141:290–303.

  24. 24

    Russell RC, Yuan H-X, Guan K-L. Autophagy regulation by nutrient signaling. Cell Res. 2014;24:42–57.

  25. 25

    Mitchener JS, Shelburne JD, Bradford WD, Hawkins HK. Cellular autophagocytosis induced by deprivation of serum and amino acids in HeLa cells. Am J Pathol. 1976;83:485–92.

  26. 26

    Mortimore GE, Schworer CM. Induction of autophagy by amino-acid deprivation in perfused rat liver. Nature. 1977;270:174–6.

  27. 27

    Noda T, Ohsumi Y. Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem. 1998;273:3963–6.

  28. 28

    Scott RC, Schuldiner O, Neufeld TP. Role and regulation of starvation-induced autophagy in the Drosophila fat body. Dev Cell. 2004;7:167–78.

  29. 29

    Gallagher LE, Chan EY. Early signalling events of autophagy. Essays Biochem. 2013;55:1–15.

  30. 30

    Tooze SA, Yoshimori T. The origin of the autophagosomal membrane. Nat Cell Biol. 2010;12:831–5.

  31. 31

    Simonsen A, Tooze SA. Coordination of membrane events during autophagy by multiple class III PI3-kinase complexes. J Cell Biol. 2009;186:773–82.

  32. 32

    Lamb CA, Yoshimori T, Tooze SA. The autophagosome: origins unknown, biogenesis complex. Nat Rev Mol Cell Biol. 2013;14:759–74.

  33. 33

    Nakatogawa H. Two ubiquitin-like conjugation systems that mediate membrane formation during autophagy. Essays Biochem. 2013;55:39–50.

  34. 34

    Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell. 2008;19:2092–100.

  35. 35

    Dooley HC, Razi M, Polson HE, Girardin SE, Wilson MI, Tooze SA. WIPI2 links LC3 conjugation with PI3P, autophagosome formation, and pathogen clearance by recruiting Atg12-5-16L1. Mol Cell. 2014;55:238–52.

  36. 36

    Satoo K, Noda NN, Kumeta H, Fujioka Y, Mizushima N, Ohsumi Y, et al. The structure of Atg4B-LC3 complex reveals the mechanism of LC3 processing and delipidation during autophagy. EMBO J. 2009;28:1341–50.

  37. 37

    Schaaf MB, Keulers TG, Vooijs MA, Rouschop KM. LC3/GABARAP family proteins: autophagy-(un)related functions. FASEB J. 2016;30:3961–78.

  38. 38

    Tanida I, Ueno T, Kominami E. LC3 conjugation system in mammalian autophagy. Int J Biochem Cell Biol. 2004;36:2503–18.

  39. 39

    Ganley IG. Autophagosome maturation and lysosomal fusion. Essays Biochem. 2013;55:65–78.

  40. 40

    Eskelinen E-L. Maturation of autophagic vacuoles in mammalian cells. Autophagy. 2004;1:1–10.

  41. 41

    Gutierrez MG, Munafó DB, Berón W, Colombo MI. Rab7 is required for the normal progression of the autophagic pathway in mammalian cells. J Cell Sci. 2004;117:2687–97.

  42. 42

    Itakura E, Kishi-Itakura C, Mizushima N. The hairpin-type tail-anchored SNARE syntaxin 17 targets to autophagosomes for fusion with endosomes/lysosomes. Cell. 2012;151:1256–69.

  43. 43

    Jiang P, Nishimura T, Sakamaki Y, Itakura E, Hatta T, Natsume T, et al. The HOPS complex mediates autophagosome–lysosome fusion through interaction with syntaxin 17. Mol Biol Cell. 2014;25:1327–37.

  44. 44

    Boya P, Gonzalez-Polo RA, Casares N, Perfettini JL, Dessen P, Larochette N, et al. Inhibition of macroautophagy triggers apoptosis. Mol Cell Biol. 2005;25:1025–40.

  45. 45

    Yamamoto A, Tagawa Y, Yoshimori T, Moriyama Y, Masaki R, Tashiro Y. Bafilomycin A1 prevents maturation of autophagic vacuoles by inhibiting fusion between autophagosomes and lysosomes in rat hepatoma cell line, H-4-II-E cells. Cell Struct Funct. 1998;23:33–42.

  46. 46

    Doi S, Tanabe K, Watanabe M, Yoshimura M. Chloroquine, a lysosomotropic agent, inhibits zygote formation in yeast. Arch Microbiol. 1989;151:20–25.

  47. 47

    Mauvezin C, Neufeld TP. Bafilomycin A1 disrupts autophagic flux by inhibiting both V-ATPase-dependent acidification and Ca-P60A/SERCA-dependent autophagosome-lysosome fusion. Autophagy. 2015;11:1437–8.

  48. 48

    Eskelinen EL, Tanaka Y, Saftig P. At the acidic edge: emerging functions for lysosomal membrane proteins. Trends Cell Biol. 2003;13:137–45.

  49. 49

    Khaminets A, Behl C, Dikic I. Ubiquitin-dependent and independent signals in selective autophagy. Trends Cell Biol. 2016;26:6–16.

  50. 50

    Stolz A, Ernst A, Dikic I. Cargo recognition and trafficking in selective autophagy. Nat Cell Biol. 2014;16:495–501.

  51. 51

    Settembre C, Di Malta C, Polito VA, Garcia Arencibia M, Vetrini F, Erdin S, et al. TFEB links autophagy to lysosomal biogenesis. Science. 2011;332:1429–33.

  52. 52

    Chauhan S, Goodwin JG, Chauhan S, Manyam G, Wang J, Kamat AM, et al. ZKSCAN3 is a master transcriptional repressor of autophagy. Mol Cell. 2013;50:16–28.

  53. 53

    Fullgrabe J, Klionsky DJ, Joseph B. The return of the nucleus: transcriptional and epigenetic control of autophagy. Nat Rev Mol Cell Biol. 2014;15:65–74.

  54. 54

    Shin HJ, Kim H, Oh S, Lee JG, Kee M, Ko HJ, et al. AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy. Nature. 2016;534:553–7.

  55. 55

    Selvi BR, Batta K, Kishore AH, Mantelingu K, Varier RA, Balasubramanyam K, et al. Identification of a novel inhibitor of coactivator-associated arginine methyltransferase 1 (CARM1)-mediated methylation of histone H3 Arg-17. J Biol Chem. 2010;285:7143–52.

  56. 56

    Fullgrabe J, Lynch-Day MA, Heldring N, Li W, Struijk RB, Ma Q, et al. The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Nature. 2013;500:468–71.

  57. 57

    Huang R, Xu Y, Wan W, Shou X, Qian J, You Z et al. Deacetylation of nuclear LC3 drives autophagy initiation under starvation. Mol Cell. 2015;57:456–66.

  58. 58

    Artal-Martinez de Narvajas A, Gomez TS, Zhang JS, Mann AO, Taoda Y, Gorman JA, et al. Epigenetic regulation of autophagy by the methyltransferase G9a. Mol Cell Biol. 2013;33:3983–93.

  59. 59

    Wei F-Z, Cao Z, Wang X, Wang H, Cai M-Y, Li T, et al. Epigenetic regulation of autophagy by the methyltransferase EZH2 through an MTOR-dependent pathway. Autophagy. 2015;11:2309–22.

  60. 60

    Eisenberg-Lerner A, Kimchi A. The paradox of autophagy and its implication in cancer etiology and therapy. Apoptosis. 2009;14:376–91.

  61. 61

    White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012;12:401–10.

  62. 62

    Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011;10:1533–41.

  63. 63

    Kung CP, Budina A, Balaburski G, Bergenstock MK, Murphy M. Autophagy in tumor suppression and cancer therapy. Crit Rev Eukaryot Gene Expr. 2011;21:71–100.

  64. 64

    Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402:672–6.

  65. 65

    Shen Y, Li DD, Wang LL, Deng R, Zhu XF. Decreased expression of autophagy-related proteins in malignant epithelial ovarian cancer. Autophagy. 2008;4:1067–8.

  66. 66

    Furuya N, Yu J, Byfield M, Pattingre S, Levine B. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy. 2005;1:46–52.

  67. 67

    Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol. 2007;9:1142–51.

  68. 68

    Takamura A, Komatsu M, Hara T, Sakamoto A, Kishi C, Waguri S, et al. Autophagy-deficient mice develop multiple liver tumors. Genes Dev. 2011;25:795–800.

  69. 69

    Kimmelman AC. The dynamic nature of autophagy in cancer. Genes Dev. 2011;25:1999–2010.

  70. 70

    Noguchi M, Hirata N, Suizu F. The links between AKT and two intracellular proteolytic cascades: ubiquitination and autophagy. Biochim Biophys Acta. 2014;1846:342–52.

  71. 71

    Roy S, Debnath J. Autophagy and tumorigenesis. Semin Immunopathol. 2010;32:383–96.

  72. 72

    Errafiy R, Aguado C, Ghislat G, Esteve JM, Gil A, Loutfi M, et al. PTEN increases autophagy and inhibits the ubiquitin-proteasome pathway in glioma cells independently of its lipid phosphatase activity. PLoS ONE. 2013;8:e83318.

  73. 73

    Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, Chen HY et al. Autophagy suppresses tumorigenesis through elimination of p62. Cell. 2009;137:1062–75.

  74. 74

    Liu EY, Ryan KM. Autophagy and cancer – issues we need to digest. J Cell Sci. 2012;125:2349–58.

  75. 75

    Wei H, Wei S, Gan B, Peng X, Zou W, Guan J-L. Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes Dev. 2011;25:1510–27.

  76. 76

    Kim M-J, Woo S-J, Yoon C-H, Lee J-S, An S, Choi Y-H, et al. Involvement of autophagy in oncogenic K-Ras-induced malignant cell transformation. J Biol Chem. 2011;286:12924–32.

  77. 77

    Yang S, Wang X, Contino G, Liesa M, Sahin E, Ying H, et al. Pancreatic cancers require autophagy for tumor growth. Genes Dev. 2011;25:717–29.

  78. 78

    Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000; 100: 57–70.

  79. 79

    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; 144:646–74.

  80. 80

    Yang ZJ, Chee CE, Huang S, Sinicrope FA. The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther. 2011;10:1533–41.

  81. 81

    Cianfanelli V, Fuoco C, Lorente M, Salazar M, Quondamatteo F, Gherardini PF, et al. AMBRA1 links autophagy to cell proliferation and tumorigenesis by promoting c-Myc dephosphorylation and degradation. Nat Cell Biol. 2015;17:706.

  82. 82

    Guo JY, Karsli-Uzunbas G, Mathew R, Aisner SC, Kamphorst JJ, Strohecker AM, et al. Autophagy suppresses progression of K-ras-induced lung tumors to oncocytomas and maintains lipid homeostasis. Genes Dev. 2013;27:1447–61.

  83. 83

    Chatterjee A, Mukhopadhyay S, Tung K, Patel D, Foster DA. Rapamycin-induced G1 cell cycle arrest employs both TGF-β and Rb pathways. Cancer Lett. 2015;360:134–40.

  84. 84

    Yazbeck VY, Buglio D, Georgakis GV, Li Y, Iwado E, Romaguera JE, et al. Temsirolimus downregulates p21 without altering cyclin D1 expression and induces autophagy and synergizes with vorinostat in mantle cell lymphoma. Exp Hematol. 2008;36:443–50.

  85. 85

    Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401–10.

  86. 86

    Cavallaro U, Christofori G. Molecular mechanisms of tumor angiogenesis and tumor progression. J Neurooncol. 2000;50:63–70.

  87. 87

    Meadows KL, Hurwitz HI. Anti-VEGF therapies in the clinic. Cold Spring Harb Perspect Med. 2012;2.

  88. 88

    Hu YL, DeLay M, Jahangiri A, Molinaro AM, Rose SD, Carbonell WS, et al. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res. 2012;72:1773–83.

  89. 89

    Nishikawa T, Tsuno NH, Okaji Y, Sunami E, Shuno Y, Sasaki K, et al. The inhibition of autophagy potentiates anti-angiogenic effects of sulforaphane by inducing apoptosis. Angiogenesis. 2010;13:227–38.

  90. 90

    Ramakrishnan S, Nguyen TM, Subramanian IV, Kelekar A. Autophagy and angiogenesis inhibition. Autophagy. 2007;3:512–5.

  91. 91

    Kim KW, Paul P, Qiao J, Lee S, Chung DH. Enhanced autophagy blocks angiogenesis via degradation of gastrin-releasing peptide in neuroblastoma cells. Autophagy. 2013;9:1579–90.

  92. 92

    Kenific CM, Thorburn A, Debnath J. Autophagy and metastasis: another double-edged sword. Curr Opin Cell Biol. 2010;22:241–5.

  93. 93

    Qiang L, Zhao B, Ming M, Wang N, He TC, Hwang S, et al. Regulation of cell proliferation and migration by p62 through stabilization of Twist1. Proc Natl Acad Sci USA. 2014;111:9241–6.

  94. 94

    Gilmore AP. Anoikis. Cell Death Differ. 2005;12(Suppl 2):1473–7.

  95. 95

    Guadamillas MC, Cerezo A, Del Pozo MA. Overcoming anoikis--pathways to anchorage-independent growth in cancer. J Cell Sci. 2011;124:3189–97.

  96. 96

    Li J, Yang B, Zhou Q, Wu Y, Shang D, Guo Y, et al. Autophagy promotes hepatocellular carcinoma cell invasion through activation of epithelial-mesenchymal transition. Carcinogenesis. 2013;34:1343–51.

  97. 97

    Zhai H, Fesler A, Ba Y, Wu S, Ju J. Inhibition of colorectal cancer stem cell survival and invasive potential by hsa-miR-140-5p mediated suppression of Smad2 and autophagy. Oncotarget. 2015;6:19735–46.

  98. 98

    Lane DP. Cancer. p53, guardian of the genome. Nature. 1992;358:15–16.

  99. 99

    Fernald K, Kurokawa M. Evading apoptosis in cancer. Trends Cell Biol. 2013;23:620–33.

  100. 100

    Hanahan D, Weinberg Robert A. Hallmarks of cancer: The next generation. Cell. 2011;144:646-74.

  101. 101

    Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005;122:927–39.

  102. 102

    Levine B, Yuan J. Autophagy in cell death: an innocent convict? J Clin Invest 2005;115:2679–88.

  103. 103

    Josset E, Burckel H, Noel G, Bischoff P. The mTOR inhibitor RAD001 potentiates autophagic cell death induced by temozolomide in a glioblastoma cell line. Anticancer Res. 2013;33:1845–51.

  104. 104

    Kanzawa T, Kondo Y, Ito H, Kondo S, Germano I. Induction of autophagic cell death in malignant glioma cells by arsenic trioxide. Cancer Res. 2003;63:2103–8.

  105. 105

    Kohli L, Kaza N, Coric T, Byer SJ, Brossier NM, Klocke BJ, et al. 4-Hydroxytamoxifen induces autophagic death through K-Ras degradation. Cancer Res. 2013;73:4395–405.

  106. 106

    Salazar M, Carracedo A, Salanueva IJ, Hernandez-Tiedra S, Lorente M, Egia A, et al. Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest. 2009;119:1359–72.

  107. 107

    Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell. 2012;21:297–308.

  108. 108

    White E. Exploiting the bad eating habits of Ras-driven cancers. Genes Dev. 2013;27:2065–71.

  109. 109

    Kenific CM, Debnath J. Cellular and metabolic functions for autophagy in cancer cells. Trends Cell Biol. 2015;25:37–45.

  110. 110

    Cook KL, Shajahan AN, Clarke R. Autophagy and endocrine resistance in breast cancer. Expert Rev Anticancer Ther. 2011;11:1283–94.

  111. 111

    Jain K, Paranandi KS, Sridharan S, Basu A. Autophagy in breast cancer and its implications for therapy. Am J Cancer Res. 2013;3:251–65.

  112. 112

    Wang J, Wu GS. Role of autophagy in cisplatin resistance in ovarian cancer cells. J Biol Chem. 2014;289:17163–73.

  113. 113

    Sui X, Chen R, Wang Z, Huang Z, Kong N, Zhang M, et al. Autophagy and chemotherapy resistance: a promising therapeutic target for cancer treatment. Cell Death Dis. 2013;4:e838.

  114. 114

    Y-p Yang, L-f Hu, H-f Zheng, C-j Mao, W-d Hu, K-p Xiong, et al. Application and interpretation of current autophagy inhibitors and activators. Acta Pharmacol Sin. 2013;34:625–35.

  115. 115

    Song J, Qu Z, Guo X, Zhao Q, Zhao X, Gao L, et al. Hypoxia-induced autophagy contributes to the chemoresistance of hepatocellular carcinoma cells. Autophagy. 2009;5:1131–44.

  116. 116

    Selvakumaran M, Amaravadi RK, Vasilevskaya IA, O’Dwyer PJ. Autophagy inhibition sensitizes colon cancer cells to antiangiogenic and cytotoxic therapy. Clin Cancer Res. 2013;19:2995–3007.

  117. 117

    Crazzolara R, Cisterne A, Thien M, Hewson J, Baraz R, Bradstock KF, et al. Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia. Blood. 2009;113:3297–306.

  118. 118

    Milano V, Piao Y, LaFortune T, de Groot J. Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma. Mol Cancer Ther. 2009;8:394–406.

  119. 119

    Liu YL, Yang PM, Shun CT, Wu MS, Weng JR, Chen CC. Autophagy potentiates the anti-cancer effects of the histone deacetylase inhibitors in hepatocellular carcinoma. Autophagy. 2010;6:1057–65.

  120. 120

    Shao Y, Gao Z, Marks PA, Jiang X. Apoptotic and autophagic cell death induced by histone deacetylase inhibitors. Proc Natl Acad Sci USA. 2004;101:18030–5.

  121. 121

    Guba M, von Breitenbuch P, Steinbauer M, Koehl G, Flegel S, Hornung M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8:128–35.

  122. 122

    Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449–56.

  123. 123

    Copeland RA, Solomon ME, Richon VM. Protein methyltransferases as a target class for drug discovery. Nat Rev Drug Discov. 2009;8:724–32.

  124. 124

    Chung YC, Lu LC, Tsai MH, Chen YJ, Chen YY, Yao SP, et al. The inhibitory effect of ellagic acid on cell growth of ovarian carcinoma cells. Evid Based Complement Altern Med. 2013;2013:306705.

  125. 125

    Hsieh YY, Lo HL, Yang PM. EZH2 inhibitors transcriptionally upregulate cytotoxic autophagy and cytoprotective unfolded protein response in human colorectal cancer cells. Am J Cancer Res. 2016;6:1661–80.

  126. 126

    He S, Zhao Z, Yang Y, O’Connell D, Zhang X, Oh S, et al. Truncating mutation in the autophagy gene UVRAG confers oncogenic properties and chemosensitivity in colorectal cancers. Nat Commun. 2015;6:7839.

  127. 127

    Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490:61–70.

  128. 128

    Cancer Genome Atlas N. Comprehensive molecular characterization of human colon and rectal cancer. Nature. 2012;487:330–7.

  129. 129

    Cancer Genome Atlas N. Integrated genomic analyses of ovarian carcinoma. Nature. 2011;474:609–15.

  130. 130

    Cancer Genome Atlas N. Comprehensive genomic characterization of squamous cell lung cancers. Nature. 2012;489:519–25.

  131. 131

    Cancer Genome Atlas N. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50.

  132. 132

    Cancer Genome Atlas N. The molecular taxonomy of primary prostate. Cancer Cell. 2015;163:1011–25.

  133. 133

    Rebecca VW, Amaravadi RK. Emerging strategies to effectively target autophagy in cancer. Oncogene. 2016;35:1–11.

Download references

Acknowledgements

APK was supported by grants from National Medical Research Council of Singapore, NCIS Yong Siew Yoon Research Grant through donations from the Yong Loo Lin Trust and by the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centers of Excellence initiative to Cancer Science Institute of Singapore, National University of Singapore. This work was also supported by Wellcome Trust/DBT India Alliance Intermediate Fellowship (509159/Z/09/Z) and JNCASR intramural funds to RM. The JNCASR doctoral fellowship to SV is also acknowledged. We also thank Dr. Prathibha Ranganathan (Centre for Human Genetics, Bengaluru), Aparna Hebbar and members of Autophagy lab (JNCASR) for critical reading of the manuscript. This work was supported by NUHS Basic seed grant [T1-BSRG 2015-02] and Ministry of Education Tier 1 grant to GS. The John Nott Cancer Fellowship from Cancer Council, Western Australia also supported GS. This work is supported in part by National Medical Research Council Singapore (NMRC) grants (NMRC-CIRG/1346/2012 and NMRC/CIRG/1373/2013) to HMS.

Author information

Author notes

    Affiliations

    1. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore

      • Shikha Satendra Singh
      • , Tuan Zea Tan
      • , Boon Cher Goh
      • , Ruby Yun-Ju Huang
      •  & Alan Prem Kumar
    2. Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

      • Shikha Satendra Singh
      • , Amelia Yi-Qian Chia
      • , Boon Cher Goh
      • , Gautam Sethi
      •  & Alan Prem Kumar
    3. Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, Karnataka, India

      • Somya Vats
      •  & Ravi Manjithaya
    4. Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

      • Shuo Deng
      • , Mei Shan Ong
      • , Celestial T. Yap
      •  & Han Ming Shen
    5. Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia

      • Frank Arfuso
    6. Department of Haematology-Oncology, National University Hospital, National University Health System, Singapore, Singapore

      • Boon Cher Goh
    7. National University Cancer Institute, National University Health System, Singapore, Singapore

      • Boon Cher Goh
      •  & Alan Prem Kumar
    8. School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia

      • Gautam Sethi
    9. Department of Obstetrics and Gynaecology, National University Health System, Singapore, Singapore

      • Ruby Yun-Ju Huang
    10. Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

      • Ruby Yun-Ju Huang
    11. NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore, Singapore

      • Han Ming Shen
    12. Curtin Medical School, Faculty of Health Sciences, Curtin University, Perth, WA, Australia

      • Alan Prem Kumar
    13. Medical Science Cluster, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

      • Alan Prem Kumar

    Authors

    1. Search for Shikha Satendra Singh in:

    2. Search for Somya Vats in:

    3. Search for Amelia Yi-Qian Chia in:

    4. Search for Tuan Zea Tan in:

    5. Search for Shuo Deng in:

    6. Search for Mei Shan Ong in:

    7. Search for Frank Arfuso in:

    8. Search for Celestial T. Yap in:

    9. Search for Boon Cher Goh in:

    10. Search for Gautam Sethi in:

    11. Search for Ruby Yun-Ju Huang in:

    12. Search for Han Ming Shen in:

    13. Search for Ravi Manjithaya in:

    14. Search for Alan Prem Kumar in:

    Conflict of interest

    The authors declare that they have no competing interests.

    Corresponding authors

    Correspondence to Ravi Manjithaya or Alan Prem Kumar.

    Electronic supplementary material

    About this article

    Publication history

    Received

    Revised

    Accepted

    Published

    DOI

    https://doi.org/10.1038/s41388-017-0046-6