All Title Author
Keywords Abstract

PLOS Genetics  2014 

Maf1 Is a Novel Target of PTEN and PI3K Signaling That Negatively Regulates Oncogenesis and Lipid Metabolism

DOI: doi/10.1371/journal.pgen.1004789

Full-Text   Cite this paper   Add to My Lib


Maf1 was initially identified as a transcriptional repressor of RNA pol III-transcribed genes, yet little is known about its other potential target genes or its biological function. Here, we show that Maf1 is a key downstream target of PTEN that drives both its tumor suppressor and metabolic functions. Maf1 expression is diminished with loss of PTEN in both mouse models and human cancers. Consistent with its role as a tumor suppressor, Maf1 reduces anchorage-independent growth and tumor formation in mice. PTEN-mediated changes in Maf1 expression are mediated by PTEN acting on PI3K/AKT/FoxO1 signaling, revealing a new pathway that regulates RNA pol III-dependent genes. This regulatory event is biologically relevant as diet-induced PI3K activation reduces Maf1 expression in mouse liver. We further identify lipogenic enzymes as a new class of Maf1-regulated genes whereby Maf1 occupancy at the FASN promoter opposes SREBP1c-mediated transcription activation. Consistent with these findings, Maf1 inhibits intracellular lipid accumulation and increasing Maf1 expression in mouse liver abrogates diet-mediated induction of lipogenic enzymes and triglycerides. Together, these results establish a new biological role for Maf1 as a downstream effector of PTEN/PI3K signaling and reveal that Maf1 is a key element by which this pathway co-regulates lipid metabolism and oncogenesis.


[1]  Eheman C, Henley SJ, Ballard-Barbash R, Jacobs EJ, Schymura MJ, et al. (2012) Annual Report to the Nation on the status of cancer, 1975-2008, featuring cancers associated with excess weight and lack of sufficient physical activity. Cancer 118: 2338–2366.
[2]  Furuta E, Okuda H, Kobayashi A, Watabe K (2010) Metabolic genes in cancer: their roles in tumor progression and clinical implications. Biochim Biophys Acta 1805: 141–152.
[3]  Menendez JA, Lupu R (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7: 763–777.
[4]  Flavin R, Peluso S, Nguyen PL, Loda M (2010) Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol 6: 551–562.
[5]  Hollander MC, Blumenthal GM, Dennis PA (2011) PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 11: 289–301.
[6]  Krycer JR, Sharpe LJ, Luu W, Brown AJ (2010) The Akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrinol Metab 21: 268–276.
[7]  Upadhya R, Lee J, Willis IM (2002) Maf1 is an essential mediator of diverse signals that repress RNA polymerase III transcription. Mol Cell 10: 1489–1494.
[8]  Vannini A, Ringel R, Kusser AG, Berninghausen O, Kassavetis GA, et al. (2010) Molecular basis of RNA polymerase III transcription repression by Maf1. Cell 143: 59–70.
[9]  Johnson SS, Zhang C, Fromm J, Willis IM, Johnson DL (2007) Mammalian Maf1 is a negative regulator of transcription by all three nuclear RNA polymerases. Mol Cell 26: 367–379.
[10]  Zhong S, Fromm J, Johnson DL (2007) TBP is differentially regulated by c-Jun N-terminal kinase 1 (JNK1) and JNK2 through Elk-1, controlling c-Jun expression and cell proliferation. Mol Cell Biol 27: 54–64.
[11]  Johnson SA, Dubeau L, Kawalek M, Dervan A, Schonthal AH, et al. (2003) Increased expression of TATA-binding protein, the central transcription factor, can contribute to oncogenesis. Mol Cell Biol 23: 3043–3051.
[12]  Johnson SA, Dubeau L, Johnson DL (2008) Enhanced RNA polymerase III-dependent transcription is required for oncogenic transformation. J Biol Chem 283: 19184–19191.
[13]  Johnson DL, Johnson SA (2008) Cell biology. RNA metabolism and oncogenesis. Science 320: 461–462.
[14]  Stiles B, Wang Y, Stahl A, Bassilian S, Lee WP, et al. (2004) Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity [corrected]. Proc Natl Acad Sci U S A 101: 2082–2087.
[15]  Wang S, Gao J, Lei Q, Rozengurt N, Pritchard C, et al. (2003) Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4: 209–221.
[16]  Strable MS, Ntambi JM (2010) Genetic control of de novo lipogenesis: role in diet-induced obesity. Crit Rev Biochem Mol Biol 45: 199–214.
[17]  Nakae J, Oki M, Cao Y (2008) The FoxO transcription factors and metabolic regulation. FEBS Lett 582: 54–67.
[18]  Woiwode A, Johnson SA, Zhong S, Zhang C, Roeder RG, et al. (2008) PTEN represses RNA polymerase III-dependent transcription by targeting the TFIIIB complex. Mol Cell Biol 28: 4204–4214.
[19]  Marshall L, Kenneth NS, White RJ (2008) Elevated tRNA(iMet) synthesis can drive cell proliferation and oncogenic transformation. Cell 133: 78–89.
[20]  Ferramosca A, Zara V (2014) Modulation of hepatic steatosis by dietary fatty acids. World J Gastroenterol 20: 1746–1755.
[21]  Peyrou M, Bourgoin L, Foti M (2010) PTEN in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and cancer. Dig Dis 28: 236–246.
[22]  Vinciguerra M, Veyrat-Durebex C, Moukil MA, Rubbia-Brandt L, Rohner-Jeanrenaud F, et al. (2008) PTEN down-regulation by unsaturated fatty acids triggers hepatic steatosis via an NF-kappaBp65/mTOR-dependent mechanism. Gastroenterology 134: 268–280.
[23]  Leavens KF, Easton RM, Shulman GI, Previs SF, Birnbaum MJ (2009) Akt2 is required for hepatic lipid accumulation in models of insulin resistance. Cell Metab 10: 405–418.
[24]  He L, Hou X, Kanel G, Zeng N, Galicia V, et al. (2010) The critical role of AKT2 in hepatic steatosis induced by PTEN loss. Am J Pathol 176: 2302–2308.
[25]  Lu M, Wan M, Leavens KF, Chu Q, Monks BR, et al. (2012) Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat Med 18: 388–395.
[26]  Wan M, Leavens KF, Saleh D, Easton RM, Guertin DA, et al. (2011) Postprandial hepatic lipid metabolism requires signaling through Akt2 independent of the transcription factors FoxA2, FoxO1, and SREBP1c. Cell Metab 14: 516–527.
[27]  Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, et al. (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8: 224–236.
[28]  Yecies JL, Zhang HH, Menon S, Liu S, Yecies D, et al. (2011) Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab 14: 21–32.
[29]  Kamei Y, Miura S, Suganami T, Akaike F, Kanai S, et al. (2008) Regulation of SREBP1c gene expression in skeletal muscle: role of retinoid X receptor/liver X receptor and forkhead-O1 transcription factor. Endocrinology 149: 2293–2305.
[30]  Deng X, Zhang W, I OS, Williams JB, Dong Q, et al. (2012) FoxO1 inhibits sterol regulatory element-binding protein-1c (SREBP-1c) gene expression via transcription factors Sp1 and SREBP-1c. J Biol Chem 287: 20132–20143.
[31]  Michels AA, Robitaille AM, Buczynski-Ruchonnet D, Hodroj W, Reina JH, et al. (2010) mTORC1 directly phosphorylates and regulates human MAF1. Mol Cell Biol 30: 3749–3757.
[32]  Kantidakis T, Ramsbottom BA, Birch JL, Dowding SN, White RJ (2010) mTOR associates with TFIIIC, is found at tRNA and 5S rRNA genes, and targets their repressor Maf1. Proc Natl Acad Sci U S A 107: 11823–11828.
[33]  Galicia VA, He L, Dang H, Kanel G, Vendryes C, et al. (2010) Expansion of hepatic tumor progenitor cells in Pten-null mice requires liver injury and is reversed by loss of AKT2. Gastroenterology 139: 2170–2182.
[34]  Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, et al. (2004) Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 113: 1774–1783.
[35]  Mashima T, Seimiya H, Tsuruo T (2009) De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br J Cancer 100: 1369–1372.
[36]  Sun H, Lesche R, Li DM, Liliental J, Zhang H, et al. (1999) PTEN modulates cell cycle progression and cell survival by regulating phosphatidylinositol 3,4,5,-trisphosphate and Akt/protein kinase B signaling pathway. Proc Natl Acad Sci U S A 96: 6199–6204.
[37]  Xu X, Kobayashi S, Qiao W, Li C, Xiao C, et al. (2006) Induction of intrahepatic cholangiocellular carcinoma by liver-specific disruption of Smad4 and Pten in mice. J Clin Invest 116: 1843–1852.
[38]  Brunn GJ, Williams J, Sabers C, Wiederrecht G, Lawrence JC Jr, et al. (1996) Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J 15: 5256–5267.
[39]  Swinnen JV, Ulrix W, Heyns W, Verhoeven G (1997) Coordinate regulation of lipogenic gene expression by androgens: evidence for a cascade mechanism involving sterol regulatory element binding proteins. Proc Natl Acad Sci U S A 94: 12975–12980.
[40]  Lyu J, Wesselschmidt RL, Lu W (2009) Cdc37 regulates Ryk signaling by stabilizing the cleaved Ryk intracellular domain. J Biol Chem 284: 12940–12948.
[41]  Miyazaki M, Kim YC, Ntambi JM (2001) A lipogenic diet in mice with a disruption of the stearoyl-CoA desaturase 1 gene reveals a stringent requirement of endogenous monounsaturated fatty acids for triglyceride synthesis. J Lipid Res 42: 1018–1024.


comments powered by Disqus