1932

Abstract

Discovery of targeted therapies that selectively exploit the genetic inactivation of specific tumor suppressors remains a major challenge. This includes the prevalent deletion of the / locus, which was first reported nearly 40 years ago. The more recent advent of RNA interference and functional genomic screening technologies led to the identification of hidden collateral lethalities occurring with passenger deletions of in cancer cells. In particular, small-molecule inhibition of the type II arginine methyltransferase PRMT5 and the -adenosylmethionine-producing enzyme MAT2A each presents a precision medicine approach for the treatment of patients whose tumors have homozygous loss of . In this review, we highlight key aspects of MTAP, PRMT5, and MAT2A biology to provide a conceptual framework for developing novel therapeutic strategies in tumors with deletion and to summarize ongoing efforts to drug PRMT5 and MAT2A.

Keyword(s): MAT2AMTAPp16PRMT5synthetic lethal
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2021-03-04
2024-05-03
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Literature Cited

  1. Alinari L, Mahasenan KV, Yan F, Karkhanis V, Chung JH et al. 2015. Selective inhibition of protein arginine methyltransferase 5 blocks initiation and maintenance of B-cell transformation. Blood 125:2530–43
    [Google Scholar]
  2. Ancelin K, Lange UC, Hajkova P, Schneider R, Bannister AJ et al. 2006. Blimp1 associates with Prmt5 and directs histone arginine methylation in mouse germ cells. Nat. Cell Biol. 8:623–30
    [Google Scholar]
  3. Baiocchi R, Li C, Lai H, Sif S 2014. Inhibitors of PRMT5 and methods of their use Int. Patent 2014/145214 A2
  4. Barekatain Y, Yan VC, Ackroyd JJ, Poral AH, Tran T et al. 2019. Methylthioadenosine is not dramatically elevated in MTAP-homozygous deleted primary glioblastomas. bioRxiv 769885. https://doi.org/10.1101/769885
    [Crossref]
  5. Basu I, Cordovano G, Das I, Belbin TJ, Guha C, Schramm VL 2007. A transition state analogue of 5′-methylthioadenosine phosphorylase induces apoptosis in head and neck cancers. J. Biol. Chem. 282:21477–86
    [Google Scholar]
  6. Basu I, Locker J, Cassera MB, Belbin TJ, Merino EF et al. 2011. Growth and metastases of human lung cancer are inhibited in mouse xenografts by a transition state analogue of 5′-methylthioadenosine phosphorylase. J. Biol. Chem. 286:4902–11
    [Google Scholar]
  7. Bedford MT, Clarke SG. 2009. Protein arginine methylation in mammals: who, what, and why. Mol. Cell 33:1–13
    [Google Scholar]
  8. Behan FM, Iorio F, Picco G, Goncalves E, Beaver CM et al. 2019. Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens. Nature 568:511–16
    [Google Scholar]
  9. Benci JL, Johnson LR, Choa R, Xu Y, Qiu J et al. 2019. Opposing functions of interferon coordinate adaptive and innate immune responses to cancer immune checkpoint blockade. Cell 178:933–48.e14
    [Google Scholar]
  10. Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S et al. 2010. The landscape of somatic copy-number alteration across human cancers. Nature 463:899–905
    [Google Scholar]
  11. Bertino JR, Waud WR, Parker WB, Lubin M 2011. Targeting tumors that lack methylthioadenosine phosphorylase (MTAP) activity: current strategies. Cancer Biol. Ther. 11:627–32
    [Google Scholar]
  12. Bezzi M, Teo SX, Muller J, Mok WC, Sahu SK et al. 2013. Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery. Genes Dev 27:1903–16
    [Google Scholar]
  13. Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN et al. 2010. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596–99
    [Google Scholar]
  14. Bonday ZQ, Cortez GS, Grogan MJ, Antonysamy S, Weichert K et al. 2018. LLY-283, a potent and selective inhibitor of arginine methyltransferase 5, PRMT5, with antitumor activity. ACS Med. Chem. Lett. 9:612–17
    [Google Scholar]
  15. Boutros M, Ahringer J. 2008. The art and design of genetic screens: RNA interference. Nat. Rev. Genet. 9:554–66
    [Google Scholar]
  16. Brahms H, Raymackers J, Union A, de Keyser F, Meheus L, Luhrmann R 2000. The C-terminal RG dipeptide repeats of the spliceosomal Sm proteins D1 and D3 contain symmetrical dimethylarginines, which form a major B-cell epitope for anti-Sm autoantibodies. J. Biol. Chem. 275:17122–29
    [Google Scholar]
  17. Braun CJ, Stanciu M, Boutz PL, Patterson JC, Calligaris D et al. 2017. Coordinated splicing of regulatory detained introns within oncogenic transcripts creates an exploitable vulnerability in malignant glioma. Cancer Cell 32:411–26.e11
    [Google Scholar]
  18. Breitinger H-G. 2012. Drug synergy—mechanisms and methods of analysis. InTech https://doi.org/10.5772/30922
    [Crossref] [Google Scholar]
  19. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D et al. 2005. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434:913–17
    [Google Scholar]
  20. Cai J, Mao Z, Hwang JJ, Lu SC 1998. Differential expression of methionine adenosyltransferase genes influences the rate of growth of human hepatocellular carcinoma cells. Cancer Res 58:1444–50
    [Google Scholar]
  21. Cai J, Sun WM, Hwang JJ, Stain SC, Lu SC 1996. Changes in S-adenosylmethionine synthetase in human liver cancer: molecular characterization and significance. Hepatology 24:1090–97
    [Google Scholar]
  22. Camacho-Vanegas O, Camacho SC, Till J, Miranda-Lorenzo I, Terzo E et al. 2012. Primate genome gain and loss: a bone dysplasia, muscular dystrophy, and bone cancer syndrome resulting from mutated retroviral-derived MTAP transcripts. Am. J. Hum. Genet. 90:614–27
    [Google Scholar]
  23. Casero RA Jr, Murray Stewart T, Pegg AE. 2018. Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat. Rev. Cancer 18:681–95
    [Google Scholar]
  24. Cen L, Carlson BL, Schroeder MA, Ostrem JL, Kitange GJ et al. 2012. p16-Cdk4-Rb axis controls sensitivity to a cyclin-dependent kinase inhibitor PD0332991 in glioblastoma xenograft cells. Neuro-Oncology 14:870–81
    [Google Scholar]
  25. Chan-Penebre E, Kuplast KG, Majer CR, Boriack-Sjodin PA, Wigle TJ et al. 2015. A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models. Nat. Chem. Biol. 11:432–37
    [Google Scholar]
  26. Chen H, Xia M, Lin M, Yang H, Kuhlenkamp J et al. 2007. Role of methionine adenosyltransferase 2A and S-adenosylmethionine in mitogen-induced growth of human colon cancer cells. Gastroenterology 133:207–18
    [Google Scholar]
  27. Chen ZH, Olopade OI, Savarese TM 1997. Expression of methylthioadenosine phosphorylase cDNA in p16, MTAP malignant cells: restoration of methylthioadenosine phosphorylase-dependent salvage pathways and alterations of sensitivity to inhibitors of purine de novo synthesis. Mol. Pharmacol. 52:903–11
    [Google Scholar]
  28. Cho EC, Zheng S, Munro S, Liu G, Carr SM et al. 2012. Arginine methylation controls growth regulation by E2F-1. EMBO J 31:1785–97
    [Google Scholar]
  29. Christopher SA, Diegelman P, Porter CW, Kruger WD 2002. Methylthioadenosine phosphorylase, a gene frequently codeleted with p16cdkN2a/ARF, acts as a tumor suppressor in a breast cancer cell line. Cancer Res 62:6639–44
    [Google Scholar]
  30. Clarke TL, Sanchez-Bailon MP, Chiang K, Reynolds JJ, Herrero-Ruiz J et al. 2017. PRMT5-dependent methylation of the TIP60 coactivator RUVBL1 is a key regulator of homologous recombination. Mol. Cell 65:900–16.e7
    [Google Scholar]
  31. Cong L, Ran FA, Cox D, Lin S, Barretto R et al. 2013. Multiplex genome engineering using CRISPR/Cas systems. Science 339:819–23
    [Google Scholar]
  32. Cowling VH. 2009. Regulation of mRNA cap methylation. Biochem. J. 425:295–302
    [Google Scholar]
  33. Cristini A, Ricci G, Britton S, Salimbeni S, Huang SN et al. 2019. Dual processing of R-loops and topoisomerase I induces transcription-dependent DNA double-strand breaks. Cell Rep 28:3167–81.e6
    [Google Scholar]
  34. Di Lorenzo A, Bedford MT 2011. Histone arginine methylation. FEBS Lett 585:2024–31
    [Google Scholar]
  35. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T 2001. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–98
    [Google Scholar]
  36. Enouf J, Lawrence F, Tempete C, Robert-Gero M, Lederer E 1979. Relationship between inhibition of protein methylase I and inhibition of Rous sarcoma virus-induced cell transformation. Cancer Res 39:4497–502
    [Google Scholar]
  37. Fabbrizio E, El Messaoudi S, Polanowska J, Paul C, Cook JR et al. 2002. Negative regulation of transcription by the type II arginine methyltransferase PRMT5. EMBO Rep 3:641–45
    [Google Scholar]
  38. Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA et al. 2005. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434:917–21
    [Google Scholar]
  39. Feng Y, Maity R, Whitelegge JP, Hadjikyriacou A, Li Z et al. 2013. Mammalian protein arginine methyltransferase 7 (PRMT7) specifically targets RXR sites in lysine- and arginine-rich regions. J. Biol. Chem. 288:37010–25
    [Google Scholar]
  40. Frau M, Feo F, Pascale RM 2013. Pleiotropic effects of methionine adenosyltransferases deregulation as determinants of liver cancer progression and prognosis. J. Hepatol. 59:830–41
    [Google Scholar]
  41. Friesen WJ, Paushkin S, Wyce A, Massenet S, Pesiridis GS et al. 2001. The methylosome, a 20S complex containing JBP1 and pICln, produces dimethylarginine-modified Sm proteins. Mol. Cell Biol. 21:8289–300
    [Google Scholar]
  42. Friesen WJ, Wyce A, Paushkin S, Abel L, Rappsilber J et al. 2002. A novel WD repeat protein component of the methylosome binds Sm proteins. J. Biol. Chem. 277:8243–47
    [Google Scholar]
  43. Gerhart SV, Kellner WA, Thompson C, Pappalardi MB, Zhang XP et al. 2018. Activation of the p53-MDM4 regulatory axis defines the anti-tumour response to PRMT5 inhibition through its role in regulating cellular splicing. Sci. Rep. 8:9711
    [Google Scholar]
  44. Gerstung M, Jolly C, Leshchiner I, Dentro SC, Gonzalez S et al. 2020. The evolutionary history of 2,658 cancers. Nature 578:122–28
    [Google Scholar]
  45. Girardot M, Hirasawa R, Kacem S, Fritsch L, Pontis J et al. 2014. PRMT5-mediated histone H4 arginine-3 symmetrical dimethylation marks chromatin at G + C-rich regions of the mouse genome. Nucleic Acids Res 42:235–48
    [Google Scholar]
  46. Guo Z, Zheng L, Xu H, Dai H, Zhou M et al. 2010. Methylation of FEN1 suppresses nearby phosphorylation and facilitates PCNA binding. Nat. Chem. Biol. 6:766–73
    [Google Scholar]
  47. Halim AB, LeGros L, Geller A, Kotb M 1999. Expression and functional interaction of the catalytic and regulatory subunits of human methionine adenosyltransferase in mammalian cells. J. Biol. Chem. 274:29720–25
    [Google Scholar]
  48. Hamard PJ, Santiago GE, Liu F, Karl DL, Martinez C et al. 2018. PRMT5 regulates DNA repair by controlling the alternative splicing of histone-modifying enzymes. Cell Rep 24:2643–57
    [Google Scholar]
  49. Hansen LJ, Sun R, Yang R, Singh SX, Chen LH et al. 2019. MTAP loss promotes stemness in glioblastoma and confers unique susceptibility to purine starvation. Cancer Res 79:3383–94
    [Google Scholar]
  50. He HL, Lee YE, Shiue YL, Lee SW, Chen TJ, Li CF 2015. Characterization and prognostic significance of methylthioadenosine phosphorylase deficiency in nasopharyngeal carcinoma. Medicine 94:e2271
    [Google Scholar]
  51. Henrich FC, Singer K, Poller K, Bernhardt L, Strobl CD et al. 2016. Suppressive effects of tumor cell-derived 5′-deoxy-5′-methylthioadenosine on human T cells. OncoImmunology 5:e1184802
    [Google Scholar]
  52. Hesterberg RS, Cleveland JL, Epling-Burnette PK 2018. Role of polyamines in immune cell functions. Med. Sci. 6:122
    [Google Scholar]
  53. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S et al. 2017. Long-term outcomes of imatinib treatment for chronic myeloid leukemia. N. Engl. J. Med. 376:917–27
    [Google Scholar]
  54. Hori H, Tran P, Carrera CJ, Hori Y, Rosenbach MD et al. 1996. Methylthioadenosine phosphorylase cDNA transfection alters sensitivity to depletion of purine and methionine in A549 lung cancer cells. Cancer Res 56:5653–58
    [Google Scholar]
  55. Hsu JM, Chen CT, Chou CK, Kuo HP, Li LY et al. 2011. Crosstalk between Arg 1175 methylation and Tyr 1173 phosphorylation negatively modulates EGFR-mediated ERK activation. Nat. Cell Biol. 13:174–81
    [Google Scholar]
  56. Inoue M, Okamoto K, Terashima A, Nitta T, Muro R et al. 2018. Arginine methylation controls the strength of γc-family cytokine signaling in T cell maintenance. Nat. Immunol. 19:1265–76
    [Google Scholar]
  57. Jani TS, Gobejishvili L, Hote PT, Barve AS, Joshi-Barve S et al. 2009. Inhibition of methionine adenosyltransferase II induces FasL expression, Fas-DISC formation and caspase-8-dependent apoptotic death in T leukemic cells. Cell Res 19:358–69
    [Google Scholar]
  58. Jansson M, Durant ST, Cho EC, Sheahan S, Edelmann M et al. 2008. Arginine methylation regulates the p53 response. Nat. Cell Biol. 10:1431–39
    [Google Scholar]
  59. Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E 2012. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 337:816–21
    [Google Scholar]
  60. Jinek M, East A, Cheng A, Lin S, Ma E, Doudna J 2013. RNA-programmed genome editing in human cells. eLife 2:e00471
    [Google Scholar]
  61. Jing W, Zhu H, Liu W, Zhai X, Tian H, Yu J 2020. MTAP-deficiency could predict better treatment response in advanced lung adenocarcinoma patients initially treated with pemetrexed-platinum chemotherapy and bevacizumab. Sci. Rep. 10:843
    [Google Scholar]
  62. Kadariya Y, Tang B, Wang L, Al-Saleem T, Hayakawa K et al. 2013. Germline mutations in Mtap cooperate with Myc to accelerate tumorigenesis in mice. PLOS ONE 8:e67635
    [Google Scholar]
  63. Kadariya Y, Yin B, Tang B, Shinton SA, Quinlivan EP et al. 2009. Mice heterozygous for germ-line mutations in methylthioadenosine phosphorylase (MTAP) die prematurely of T-cell lymphoma. Cancer Res 69:5961–69
    [Google Scholar]
  64. Kamatani N, Nelson-Rees WA, Carson DA 1981. Selective killing of human malignant cell lines deficient in methylthioadenosine phosphorylase, a purine metabolic enzyme. PNAS 78:1219–23
    [Google Scholar]
  65. Kamatani N, Yu AL, Carson DA 1982. Deficiency of methylthioadenosine phosphorylase in human leukemic cells in vivo. Blood 60:1387–91
    [Google Scholar]
  66. Kindler HL, Burris HA 3rd, Sandler AB, Oliff IA 2009. A phase II multicenter study of L-alanosine, a potent inhibitor of adenine biosynthesis, in patients with MTAP-deficient cancer. Investig. New Drugs 27:75–81
    [Google Scholar]
  67. Kotb M, Kredich NM. 1990. Regulation of human lymphocyte S-adenosylmethionine synthetase by product inhibition. Biochim. Biophys. Acta 1039:253–60
    [Google Scholar]
  68. Kotb M, Mudd SH, Mato JM, Geller AM, Kredich NM et al. 1997. Consensus nomenclature for the mammalian methionine adenosyltransferase genes and gene products. Trends Genet 13:51–52
    [Google Scholar]
  69. Kryukov GV, Wilson FH, Ruth JR, Paulk J, Tsherniak A et al. 2016. MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells. Science 351:1214–18
    [Google Scholar]
  70. LeGros HL Jr, Geller AM, Kotb M. 1997. Differential regulation of methionine adenosyltransferase in superantigen and mitogen stimulated human T lymphocytes. J. Biol. Chem. 272:16040–47
    [Google Scholar]
  71. Li X, Wang C, Jiang H, Luo C 2019. A patent review of arginine methyltransferase inhibitors (2010–2018). Expert Opin. Ther. Pat. 29:97–114
    [Google Scholar]
  72. Lin H, Wang M, Zhang YW, Tong S, Leal RA et al. 2019. Discovery of potent and selective covalent protein arginine methyltransferase 5 (PRMT5) inhibitors. ACS Med. Chem. Lett. 10:1033–38
    [Google Scholar]
  73. Lombardini JB, Coulter AW, Talalay P 1970. Analogues of methionine as substrates and inhibitors of the methionine adenosyltransferase reaction: deductions concerning the conformation of methionine. Mol. Pharmacol. 6:481–99
    [Google Scholar]
  74. Lombardini JB, Sufrin JR. 1983. Chemotherapeutic potential of methionine analogue inhibitors of tumor-derived methionine adenosyltransferases. Biochem. Pharmacol. 32:489–95
    [Google Scholar]
  75. Longshaw AI, Adanitsch F, Gutierrez JA, Evans GB, Tyler PC, Schramm VL 2010. Design and synthesis of potent “sulfur-free” transition state analogue inhibitors of 5′-methylthioadenosine nucleosidase and 5′-methylthioadenosine phosphorylase. J. Med. Chem. 53:6730–46
    [Google Scholar]
  76. Lu SC, Alvarez L, Huang ZZ, Chen L, An W et al. 2001. Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. PNAS 98:5560–65
    [Google Scholar]
  77. Lu SC, Mato JM. 2012. S-adenosylmethionine in liver health, injury, and cancer. Physiol. Rev. 92:1515–42
    [Google Scholar]
  78. Lubin M, Lubin A. 2009. Selective killing of tumors deficient in methylthioadenosine phosphorylase: a novel strategy. PLOS ONE 4:e5735
    [Google Scholar]
  79. Maldonado LY, Arsene D, Mato JM, Lu SC 2018. Methionine adenosyltransferases in cancers: mechanisms of dysregulation and implications for therapy. Exp. Biol. Med. 243:107–17
    [Google Scholar]
  80. Mali P, Yang L, Esvelt KM, Aach J, Guell M et al. 2013. RNA-guided human genome engineering via Cas9. Science 339:823–26
    [Google Scholar]
  81. Marjon K, Cameron MJ, Quang P, Clasquin MF, Mandley E et al. 2016. MTAP deletions in cancer create vulnerability to targeting of the MAT2A/PRMT5/RIOK1 axis. Cell Rep 15:574–87
    [Google Scholar]
  82. Martinez-Chantar ML, Corrales FJ, Martinez-Cruz LA, Garcia-Trevijano ER, Huang ZZ et al. 2002. Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. FASEB J 16:1292–94
    [Google Scholar]
  83. Mavrakis KJ, McDonald ER 3rd, Schlabach MR, Billy E, Hoffman GR et al. 2016. Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5. Science 351:1208–13
    [Google Scholar]
  84. McDonald ER 3rd, de Weck A, Schlabach MR, Billy E, Mavrakis KJ et al. 2017. Project DRIVE: a compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening. Cell 170:577–92.e10
    [Google Scholar]
  85. Meister G, Eggert C, Buhler D, Brahms H, Kambach C, Fischer U 2001. Methylation of Sm proteins by a complex containing PRMT5 and the putative U snRNP assembly factor pICln. Curr. Biol. 11:1990–94
    [Google Scholar]
  86. Mersaoui SY, Yu Z, Coulombe Y, Karam M, Busatto FF et al. 2019. Arginine methylation of the DDX5 helicase RGG/RG motif by PRMT5 regulates resolution of RNA:DNA hybrids. EMBO J 38:e100986
    [Google Scholar]
  87. Migliori V, Muller J, Phalke S, Low D, Bezzi M et al. 2012. Symmetric dimethylation of H3R2 is a newly identified histone mark that supports euchromatin maintenance. Nat. Struct. Mol. Biol. 19:136–44
    [Google Scholar]
  88. Muller FL, Aquilanti EA, DePinho RA 2015. Collateral lethality: a new therapeutic strategy in oncology. Trends Cancer 1:161–73
    [Google Scholar]
  89. Murray B, Antonyuk SV, Marina A, Lu SC, Mato JM et al. 2016. Crystallography captures catalytic steps in human methionine adenosyltransferase enzymes. PNAS 113:2104–9
    [Google Scholar]
  90. Owens JL, Beketova E, Liu S, Tinsley SL, Asberry AM et al. 2020. PRMT5 cooperates with pICln to function as a master epigenetic activator of DNA double-strand break repair genes. iScience 23:100750
    [Google Scholar]
  91. Pal S, Vishwanath SN, Erdjument-Bromage H, Tempst P, Sif S 2004. Human SWI/SNF-associated PRMT5 methylates histone H3 arginine 8 and negatively regulates expression of ST7 and NM23 tumor suppressor genes. Mol. Cell Biol. 24:9630–45
    [Google Scholar]
  92. PCAWG (Pan-Cancer Atlas Whole Genomes) Consort 2020. Pan-cancer analysis of whole genomes. Nature 578:82–93
    [Google Scholar]
  93. Pegg AE. 2016. Functions of polyamines in mammals. J. Biol. Chem. 291:14904–12
    [Google Scholar]
  94. Pendleton KE, Chen B, Liu K, Hunter OV, Xie Y et al. 2017. The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention. Cell 169:824–35.e14
    [Google Scholar]
  95. Phuong NT, Kim SK, Im JH, Yang JW, Choi MC et al. 2016. Induction of methionine adenosyltransferase 2A in tamoxifen-resistant breast cancer cells. Oncotarget 7:13902–16
    [Google Scholar]
  96. Quinlan CL, Kaiser SE, Bolanos B, Nowlin D, Grantner R et al. 2017. Targeting S-adenosylmethionine biosynthesis with a novel allosteric inhibitor of Mat2A. Nat. Chem. Biol. 13:785–92
    [Google Scholar]
  97. Radzisheuskaya A, Shliaha PV, Grinev V, Lorenzini E, Kovalchuk S et al. 2019. PRMT5 methylome profiling uncovers a direct link to splicing regulation in acute myeloid leukemia. Nat. Struct. Mol. Biol. 26:999–1012
    [Google Scholar]
  98. Roy DG, Chen J, Mamane V, Ma EH, Muhire BM et al. 2020. Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming. Cell Metab 31:250–66.e9
    [Google Scholar]
  99. Roy DM, Walsh LA, Desrichard A, Huse JT, Wu W et al. 2016. Integrated genomics for pinpointing survival loci within arm-level somatic copy number alterations. Cancer Cell 29:737–50
    [Google Scholar]
  100. Ruefli-Brasse A, Sakamoto D, Orf J, Rong MQ, Shi T et al. 2011. Methylthioadenosine (MTA) rescues methylthioadenosine phosphorylase (MTAP)-deficient tumors from purine synthesis inhibition in vivo via non-autonomous adenine supply.. J. Cancer Ther. 2:523–34
    [Google Scholar]
  101. Schmid M, Malicki D, Nobori T, Rosenbach MD, Campbell K et al. 1998. Homozygous deletions of methylthioadenosine phosphorylase (MTAP) are more frequent than p16INK4A (CDKN2) homozygous deletions in primary non-small cell lung cancers (NSCLC). Oncogene 17:2669–75
    [Google Scholar]
  102. Shaw AT, Kim DW, Mehra R, Tan DS, Felip E et al. 2014. Ceritinib in ALK-rearranged non-small-cell lung cancer. N. Engl. J. Med. 370:1189–97
    [Google Scholar]
  103. Singh V, Shi W, Evans GB, Tyler PC, Furneaux RH et al. 2004. Picomolar transition state analogue inhibitors of human 5′-methylthioadenosine phosphorylase and X-ray structure with MT-immucillin-A. Biochemistry 43:9–18
    [Google Scholar]
  104. Skourti-Stathaki K, Proudfoot NJ. 2014. A double-edged sword: R loops as threats to genome integrity and powerful regulators of gene expression. Genes Dev 28:1384–96
    [Google Scholar]
  105. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V et al. 2001. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344:783–92
    [Google Scholar]
  106. Stopa N, Krebs JE, Shechter D 2015. The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond. Cell Mol. Life Sci. 72:2041–59
    [Google Scholar]
  107. Strekalova E, Malin D, Weisenhorn EMM, Russell JD, Hoelper D et al. 2019. S-adenosylmethionine biosynthesis is a targetable metabolic vulnerability of cancer stem cells. Breast Cancer Res. Treat. 175:39–50
    [Google Scholar]
  108. Su CY, Chang YC, Chan YC, Lin TC, Huang MS et al. 2014. MTAP is an independent prognosis marker and the concordant loss of MTAP and p16 expression predicts short survival in non-small cell lung cancer patients. Eur. J. Surg. Oncol. 40:1143–50
    [Google Scholar]
  109. Sullivan DM, Hoffman JL. 1983. Fractionation and kinetic properties of rat liver and kidney methionine adenosyltransferase isozymes. Biochemistry 22:1636–41
    [Google Scholar]
  110. Sviripa VM, Zhang W, Balia AG, Tsodikov OV, Nickell JR et al. 2014. 2′,6′-Dihalostyrylanilines, pyridines, and pyrimidines for the inhibition of the catalytic subunit of methionine S-adenosyltransferase-2. J. Med. Chem. 57:6083–91
    [Google Scholar]
  111. Tan DQ, Li Y, Yang C, Li J, Tan SH et al. 2019. PRMT5 modulates splicing for genome integrity and preserves proteostasis of hematopoietic stem cells. Cell Rep 26:2316–28.e6
    [Google Scholar]
  112. Tang B, Kadariya Y, Chen Y, Slifker M, Kruger WD 2014. Expression of MTAP inhibits tumor-related phenotypes in HT1080 cells via a mechanism unrelated to its enzymatic function. G3 5:35–44
    [Google Scholar]
  113. Tao H, Yan X, Zhu K, Zhang H 2019. Discovery of novel PRMT5 inhibitors by virtual screening and biological evaluations. Chem. Pharm. Bull. 67:382–88
    [Google Scholar]
  114. Tee WW, Pardo M, Theunissen TW, Yu L, Choudhary JS et al. 2010. Prmt5 is essential for early mouse development and acts in the cytoplasm to maintain ES cell pluripotency. Genes Dev 24:2772–77
    [Google Scholar]
  115. Tomasi ML, Cossu C, Spissu Y, Floris A, Ryoo M et al. 2017. S-adenosylmethionine and methylthioadenosine inhibit cancer metastasis by targeting microRNA 34a/b-methionine adenosyltransferase 2A/2B axis. Oncotarget 8:78851–69
    [Google Scholar]
  116. Tsherniak A, Vazquez F, Montgomery PG, Weir BA, Kryukov G et al. 2017. Defining a cancer dependency map. Cell 170:564–76.e16
    [Google Scholar]
  117. Tutt AN, Lord CJ, McCabe N, Farmer H, Turner N et al. 2005. Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer. Cold Spring Harb. Symp. Quant. Biol. 70:139–48
    [Google Scholar]
  118. Vazquez-Chantada M, Fernandez-Ramos D, Embade N, Martinez-Lopez N, Varela-Rey M et al. 2010. HuR/methyl-HuR and AUF1 regulate the MAT expressed during liver proliferation, differentiation, and carcinogenesis. Gastroenterology 138:1943–53
    [Google Scholar]
  119. Wang J, Zhu ZH, Yang HB, Zhang Y, Zhao XN et al. 2016. Cullin 3 targets methionine adenosyltransferase IIα for ubiquitylation-mediated degradation and regulates colorectal cancer cell proliferation. FEBS J 283:2390–402
    [Google Scholar]
  120. Wang Y, Hu W, Yuan Y 2018. Protein arginine methyltransferase 5 (PRMT5) as an anticancer target and its inhibitor discovery. J. Med. Chem. 61:9429–41
    [Google Scholar]
  121. Wang Z, Yip LY, Lee JHJ, Wu Z, Chew HY et al. 2019. Methionine is a metabolic dependency of tumor-initiating cells. Nat. Med. 25:825–37
    [Google Scholar]
  122. Williams-Ashman HG, Seidenfeld J, Galletti P 1982. Trends in the biochemical pharmacology of 5′-deoxy-5′-methylthioadenosine. Biochem. Pharmacol. 31:277–88
    [Google Scholar]
  123. Xu J, Chang WH, Fong LWR, Weiss RH, Yu SL, Chen CH 2019. Targeting the insulin-like growth factor-1 receptor in MTAP-deficient renal cell carcinoma. Signal. Transduct. Target Ther. 4:2
    [Google Scholar]
  124. Yang HB, Xu YY, Zhao XN, Zou SW, Zhang Y et al. 2015. Acetylation of MAT IIα represses tumour cell growth and is decreased in human hepatocellular cancer. Nat. Commun. 6:6973
    [Google Scholar]
  125. Young RJ, Waldeck K, Martin C, Foo JH, Cameron DP et al. 2014. Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. Pigment Cell Melanoma Res 27:590–600
    [Google Scholar]
  126. Zappia V, Della Ragione F, Pontoni G, Gragnaniello V, Carteni-Farina M 1988. Human 5′-deoxy-5′-methylthioadenosine phosphorylase: kinetic studies and catalytic mechanism. Adv. Exp. Med. Biol. 250:165–77
    [Google Scholar]
  127. Zhang H, Chen ZH, Savarese TM 1996. Codeletion of the genes for p16INK4, methylthioadenosine phosphorylase, interferon-α1, interferon-β1, and other 9p21 markers in human malignant cell lines. Cancer Genet. Cytogenet. 86:22–28
    [Google Scholar]
  128. Zhang L, Ma S, Song X, Han B, Cheng Y et al. 2012. Gefitinib versus placebo as maintenance therapy in patients with locally advanced or metastatic non-small-cell lung cancer (INFORM; C-TONG 0804): a multicentre, double-blind randomised phase 3 trial. Lancet Oncol 13:466–75
    [Google Scholar]
  129. Zhang T, Zheng Z, Liu Y, Zhang J, Zhao Y et al. 2013. Overexpression of methionine adenosyltransferase II alpha (MAT2A) in gastric cancer and induction of cell cycle arrest and apoptosis in SGC-7901 cells by shRNA-mediated silencing of MAT2A gene. Acta Histochem 115:48–55
    [Google Scholar]
  130. Zhang W, Sviripa V, Chen X, Shi J, Yu T et al. 2013. Fluorinated N,N-dialkylaminostilbenes repress colon cancer by targeting methionine S-adenosyltransferase 2A. ACS Chem. Biol. 8:796–803
    [Google Scholar]
  131. Zhao DY, Gish G, Braunschweig U, Li Y, Ni Z et al. 2016. SMN and symmetric arginine dimethylation of RNA polymerase II C-terminal domain control termination. Nature 529:48–53
    [Google Scholar]
  132. Zhao Q, Rank G, Tan YT, Li H, Moritz RL et al. 2009. PRMT5-mediated methylation of histone H4R3 recruits DNMT3A, coupling histone and DNA methylation in gene silencing. Nat. Struct. Mol. Biol. 16:304–11
    [Google Scholar]
  133. Zheng S, Moehlenbrink J, Lu YC, Zalmas LP, Sagum CA et al. 2013. Arginine methylation-dependent reader-writer interplay governs growth control by E2F-1. Mol. Cell 52:37–51
    [Google Scholar]
  134. Zhu F, Rui L. 2019. PRMT5 in gene regulation and hematologic malignancies. Genes Dis 6:247–57
    [Google Scholar]
  135. Zhu K, Shao J, Tao H, Yan X, Luo C et al. 2019. Rational design, synthesis and biological evaluation of novel triazole derivatives as potent and selective PRMT5 inhibitors with antitumor activity. J. Comput.-Aided Mol. Des. 33:775–85
    [Google Scholar]
  136. Zhu K, Song JL, Tao HR, Cheng ZQ, Jiang CS, Zhang H 2018. Discovery of new potent protein arginine methyltransferase 5 (PRMT5) inhibitors by assembly of key pharmacophores from known inhibitors. Bioorg. Med. Chem. Lett. 28:3693–99
    [Google Scholar]
/content/journals/10.1146/annurev-cancerbio-030419-033444
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