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

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Obesity is a strong risk factor for human cancers, yet the biological basis for this is unclear. In addition to aberrant growth, abnormal lipid synthesis is a hallmark of cancer cells. Our results have identified a novel role for Maf1 in suppressing both lipid biogenesis and tumor formation. Maf1 elicits these biological responses through its ability to repress genes that that synthesize lipids and regulate biosynthetic capacity. Maf1 amounts are regulated through a critical cellular pathway involving PTEN/PI3K/Akt/FoxO1, which is deregulated in many human cancers. Our results support the idea that deregulation of this pathway in cancer cells results in decreases in cellular Maf1, resulting in both abnormal growth and lipid synthesis. Thus, Maf1 represents a novel link between lipid metabolism and oncogenic transformation providing a new molecular basis for the strong association between obesity and cancer.

Vyšlo v časopise: Maf1 Is a Novel Target of PTEN and PI3K Signaling That Negatively Regulates Oncogenesis and Lipid Metabolism. PLoS Genet 10(12): e32767. doi:10.1371/journal.pgen.1004789
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004789

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Zdroje

1. EhemanC, HenleySJ, Ballard-BarbashR, JacobsEJ, SchymuraMJ, 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. FurutaE, OkudaH, KobayashiA, WatabeK (2010) Metabolic genes in cancer: their roles in tumor progression and clinical implications. Biochim Biophys Acta 1805 : 141–152.

3. MenendezJA, LupuR (2007) Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer 7 : 763–777.

4. FlavinR, PelusoS, NguyenPL, LodaM (2010) Fatty acid synthase as a potential therapeutic target in cancer. Future Oncol 6 : 551–562.

5. HollanderMC, BlumenthalGM, DennisPA (2011) PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer 11 : 289–301.

6. KrycerJR, SharpeLJ, LuuW, BrownAJ (2010) The Akt-SREBP nexus: cell signaling meets lipid metabolism. Trends Endocrinol Metab 21 : 268–276.

7. UpadhyaR, LeeJ, WillisIM (2002) Maf1 is an essential mediator of diverse signals that repress RNA polymerase III transcription. Mol Cell 10 : 1489–1494.

8. VanniniA, RingelR, KusserAG, BerninghausenO, KassavetisGA, et al. (2010) Molecular basis of RNA polymerase III transcription repression by Maf1. Cell 143 : 59–70.

9. JohnsonSS, ZhangC, FrommJ, WillisIM, JohnsonDL (2007) Mammalian Maf1 is a negative regulator of transcription by all three nuclear RNA polymerases. Mol Cell 26 : 367–379.

10. ZhongS, FrommJ, JohnsonDL (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. JohnsonSA, DubeauL, KawalekM, DervanA, SchonthalAH, et al. (2003) Increased expression of TATA-binding protein, the central transcription factor, can contribute to oncogenesis. Mol Cell Biol 23 : 3043–3051.

12. JohnsonSA, DubeauL, JohnsonDL (2008) Enhanced RNA polymerase III-dependent transcription is required for oncogenic transformation. J Biol Chem 283 : 19184–19191.

13. JohnsonDL, JohnsonSA (2008) Cell biology. RNA metabolism and oncogenesis. Science 320 : 461–462.

14. StilesB, WangY, StahlA, BassilianS, LeeWP, 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. WangS, GaoJ, LeiQ, RozengurtN, PritchardC, et al. (2003) Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4 : 209–221.

16. StrableMS, NtambiJM (2010) Genetic control of de novo lipogenesis: role in diet-induced obesity. Crit Rev Biochem Mol Biol 45 : 199–214.

17. NakaeJ, OkiM, CaoY (2008) The FoxO transcription factors and metabolic regulation. FEBS Lett 582 : 54–67.

18. WoiwodeA, JohnsonSA, ZhongS, ZhangC, RoederRG, et al. (2008) PTEN represses RNA polymerase III-dependent transcription by targeting the TFIIIB complex. Mol Cell Biol 28 : 4204–4214.

19. MarshallL, KennethNS, WhiteRJ (2008) Elevated tRNA(iMet) synthesis can drive cell proliferation and oncogenic transformation. Cell 133 : 78–89.

20. FerramoscaA, ZaraV (2014) Modulation of hepatic steatosis by dietary fatty acids. World J Gastroenterol 20 : 1746–1755.

21. PeyrouM, BourgoinL, FotiM (2010) PTEN in non-alcoholic fatty liver disease/non-alcoholic steatohepatitis and cancer. Dig Dis 28 : 236–246.

22. VinciguerraM, Veyrat-DurebexC, MoukilMA, Rubbia-BrandtL, Rohner-JeanrenaudF, 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. LeavensKF, EastonRM, ShulmanGI, PrevisSF, BirnbaumMJ (2009) Akt2 is required for hepatic lipid accumulation in models of insulin resistance. Cell Metab 10 : 405–418.

24. HeL, HouX, KanelG, ZengN, GaliciaV, et al. (2010) The critical role of AKT2 in hepatic steatosis induced by PTEN loss. Am J Pathol 176 : 2302–2308.

25. LuM, WanM, LeavensKF, ChuQ, MonksBR, et al. (2012) Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat Med 18 : 388–395.

26. WanM, LeavensKF, SalehD, EastonRM, GuertinDA, 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. PorstmannT, SantosCR, GriffithsB, CullyM, WuM, et al. (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8 : 224–236.

28. YeciesJL, ZhangHH, MenonS, LiuS, YeciesD, et al. (2011) Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab 14 : 21–32.

29. KameiY, MiuraS, SuganamiT, AkaikeF, KanaiS, 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. DengX, ZhangW, IOS, WilliamsJB, DongQ, 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. MichelsAA, RobitailleAM, Buczynski-RuchonnetD, HodrojW, ReinaJH, et al. (2010) mTORC1 directly phosphorylates and regulates human MAF1. Mol Cell Biol 30 : 3749–3757.

32. KantidakisT, RamsbottomBA, BirchJL, DowdingSN, WhiteRJ (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. GaliciaVA, HeL, DangH, KanelG, VendryesC, 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. HorieY, SuzukiA, KataokaE, SasakiT, HamadaK, et al. (2004) Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Invest 113 : 1774–1783.

35. MashimaT, SeimiyaH, TsuruoT (2009) De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br J Cancer 100 : 1369–1372.

36. SunH, LescheR, LiDM, LilientalJ, ZhangH, 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. XuX, KobayashiS, QiaoW, LiC, XiaoC, 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. BrunnGJ, WilliamsJ, SabersC, WiederrechtG, LawrenceJCJr, 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. SwinnenJV, UlrixW, HeynsW, VerhoevenG (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. LyuJ, WesselschmidtRL, LuW (2009) Cdc37 regulates Ryk signaling by stabilizing the cleaved Ryk intracellular domain. J Biol Chem 284 : 12940–12948.

41. MiyazakiM, KimYC, NtambiJM (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.