Tumor Biology

, Volume 36, Issue 6, pp 4133–4141 | Cite as

SREBP1 regulates tumorigenesis and prognosis of pancreatic cancer through targeting lipid metabolism

  • Yan Sun
  • Weiwei He
  • Man Luo
  • Yuhong Zhou
  • Guilin Chang
  • Weiying Ren
  • Kefen Wu
  • Xi Li
  • Jiping Shen
  • Xiaoping Zhao
  • Yu Hu
Research Article

Abstract

Sterol regulatory element-binding protein 1 (SREBP1) is a known transcription factor of lipogenic genes, which plays important roles in regulating de novo lipogenesis. Accumulating evidences indicate SREBP1 is involved in tumorigenesis, yet its role in pancreatic cancer remains unclear. Here, we explored the expression characteristic and function of SREBP1 in pancreatic cancer. Analysis of 60 patients with pancreatic ducat cancer showed that SREBP1 level was significantly higher in pancreatic cancer than that in adjacent normal tissues. High expression of SREBP1 predicted poor prognosis in patients with pancreatic cancer. Multivariate analysis revealed that SREBP1 was an independent factor affecting overall survival. SREBP1 silencing resulted in proliferation inhibition and induction of apoptosis in pancreatic cancer cells. Mechanistically, lipogenic genes (acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase-1 (SCD1)) and de novo lipogenesis were promoted by SREBP1. Inhibition of lipogenic genes through specific inhibitors ablated SREBP1-mediated growth regulation. Furthermore, depletion of SREBP1 could suppress lipid metabolism and tumor growth in vivo. Our results indicate that SREBP1 had important role in tumor progression and appears to be a novel prognostic marker for pancreatic cancer.

Keywords

SREBP1 Pancreatic cancer Apoptosis Prognosis Lipid metabolism 

Notes

Acknowledgments

This study was supported by research grants from National Natural Science Foundation of China (Nos. 81201532 and 81372195), Young Teacher Scientific Capability Promotion Project of Fudan University (No. 20520133490), Shanghai Pujiang Program (No. 13PJ1406000), Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (No. 1410000157),Science and Technology Commission of Shanghai Municipality (No. 134119a5600) and Shanghai Municipal Commission of Health and Family Planning (XYQ2013109).

Conflicts of interest

The authors declare no conflict of interest.

References

  1. 1.
    Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11–30. doi:10.3322/caac.21166.CrossRefPubMedGoogle Scholar
  2. 2.
    Klapman J, Malafa MP. Early detection of pancreatic cancer: why, who, and how to screen. Cancer Control. 2008;15(4):280–7.PubMedGoogle Scholar
  3. 3.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi:10.1016/j.cell.2011.02.013.CrossRefPubMedGoogle Scholar
  4. 4.
    Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell. 2012;21(3):297–308. doi:10.1016/j.ccr.2012.02.014.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Tennant DA, Duran RV, Gottlieb E. Targeting metabolic transformation for cancer therapy. Nat Rev Cancer. 2010;10(4):267–77. doi:10.1038/nrc2817.CrossRefPubMedGoogle Scholar
  6. 6.
    Sun Y, Zhao X, Zhou Y, Hu Y. miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect. Oncol Rep. 2012;28(4):1346–52. doi:10.3892/or.2012.1958.PubMedGoogle Scholar
  7. 7.
    Sun Y, Zhao X, Luo M, Zhou Y, Ren W, Wu K, et al. The pro-apoptotic role of the regulatory feedback loop between miR-124 and PKM1/HNF4alpha in colorectal cancer cells. Int J Mol Sci. 2014;15(3):4318–32. doi:10.3390/ijms15034318.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Menendez JA, Lupu R. Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nat Rev Cancer. 2007;7(10):763–77. doi:10.1038/nrc2222.CrossRefPubMedGoogle Scholar
  9. 9.
    Walter K, Hong SM, Nyhan S, Canto M, Fedarko N, Klein A, et al. Serum fatty acid synthase as a marker of pancreatic neoplasia. Cancer Epidemiol Biomarkers Prev. 2009;18(9):2380–5. doi:10.1158/1055-9965.EPI-09-0144.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Zhao X, Feng D, Wang Q, Abdulla A, Xie XJ, Zhou J, et al. Regulation of lipogenesis by cyclin-dependent kinase 8-mediated control of SREBP-1. J Clin Invest. 2012;122(7):2417–27. doi:10.1172/JCI61462.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Freed-Pastor WA, Mizuno H, Zhao X, Langerod A, Moon SH, Rodriguez-Barrueco R, et al. Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Cell. 2012;148(1–2):244–58. doi:10.1016/j.cell.2011.12.017.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Yang F, Vought BW, Satterlee JS, Walker AK, Jim Sun ZY, Watts JL, et al. An ARC/mediator subunit required for SREBP control of cholesterol and lipid homeostasis. Nature. 2006;442(7103):700–4. doi:10.1038/nature04942.CrossRefPubMedGoogle Scholar
  13. 13.
    Walker AK, Jacobs RL, Watts JL, Rottiers V, Jiang K, Finnegan DM, et al. A conserved SREBP-1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell. 2011;147(4):840–52. doi:10.1016/j.cell.2011.09.045.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest. 2002;109(9):1125–31. doi:10.1172/JCI15593.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab. 2008;8(3):224–36. doi:10.1016/j.cmet.2008.07.007.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Guo D, Bell EH, Chakravarti A. Lipid metabolism emerges as a promising target for malignant glioma therapy. CNS Oncol. 2013;2(3):289–99. doi:10.2217/cns.13.20.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Huang WC, Li X, Liu J, Lin J, Chung LW. Activation of androgen receptor, lipogenesis, and oxidative stress converged by SREBP-1 is responsible for regulating growth and progression of prostate cancer cells. Mol Cancer Res. 2012;10(1):133–42. doi:10.1158/1541-7786.MCR-11-0206.CrossRefPubMedGoogle Scholar
  18. 18.
    Ettinger SL, Sobel R, Whitmore TG, Akbari M, Bradley DR, Gleave ME, et al. Dysregulation of sterol response element-binding proteins and downstream effectors in prostate cancer during progression to androgen independence. Cancer Res. 2004;64(6):2212–21.CrossRefPubMedGoogle Scholar
  19. 19.
    Li W, Tai Y, Zhou J, Gu W, Bai Z, Zhou T, et al. Repression of endometrial tumor growth by targeting SREBP1 and lipogenesis. Cell Cycle. 2012;11(12):2348–58. doi:10.4161/cc.20811.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Sun Y, Zhao X, Yao Y, Qi X, Yuan Y, Hu Y. Connexin 43 interacts with Bax to regulate apoptosis of pancreatic cancer through a gap junction-independent pathway. Int J Oncol. 2012;41(3):941–8. doi:10.3892/ijo.2012.1524.PubMedGoogle Scholar
  21. 21.
    Zhao X, Xiaoli, Zong H, Abdulla A, Yang ES, Ji JY, et al. Inhibition of SREBP transcriptional activity by a boron-containing compound improves lipid homeostasis in diet-induced obesity. Diabetes. 2014. doi:10.2337/db13-0835.Google Scholar
  22. 22.
    Griffiths B, Lewis CA, Bensaad K, Ros S, Zhang Q, Ferber EC, et al. Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth. Cancer Metab. 2013;1(1):3. doi:10.1186/2049-3002-1-3.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Mashima T, Seimiya H, Tsuruo T. De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy. Br J Cancer. 2009;100(9):1369–72. doi:10.1038/sj.bjc.6605007.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Ameer F, Scandiuzzi L, Hasnain S, Kalbacher H, Zaidi N. De novo lipogenesis in health and disease. Metabolism. 2014;63(7):895–902. doi:10.1016/j.metabol.2014.04.003.CrossRefPubMedGoogle Scholar
  25. 25.
    Calvisi DF, Wang C, Ho C, Ladu S, Lee SA, Mattu S, et al. Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma. Gastroenterology. 2011;140(3):1071–83. doi:10.1053/j.gastro.2010.12.006.CrossRefPubMedGoogle Scholar
  26. 26.
    Yamashita T, Honda M, Takatori H, Nishino R, Minato H, Takamura H, et al. Activation of lipogenic pathway correlates with cell proliferation and poor prognosis in hepatocellular carcinoma. J Hepatol. 2009;50(1):100–10. doi:10.1016/j.jhep.2008.07.036.CrossRefPubMedGoogle Scholar
  27. 27.
    Israel M, Schwartz L. The metabolic advantage of tumor cells. Mol Cancer. 2011;10:70. doi:10.1186/1476-4598-10-70.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Swierczynski J, Hebanowska A, Sledzinski T. Role of abnormal lipid metabolism in development, progression, diagnosis and therapy of pancreatic cancer. World J Gastroenterol. 2014;20(9):2279–303. doi:10.3748/wjg.v20.i9.2279.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yan Sun
    • 1
  • Weiwei He
    • 2
  • Man Luo
    • 1
  • Yuhong Zhou
    • 3
  • Guilin Chang
    • 1
  • Weiying Ren
    • 1
  • Kefen Wu
    • 1
  • Xi Li
    • 1
  • Jiping Shen
    • 1
  • Xiaoping Zhao
    • 4
  • Yu Hu
    • 1
  1. 1.Department of Geriatrics, Zhongshan HospitalFudan UniversityShanghaiChina
  2. 2.Department of Thoracic Surgery, Sixth People’s Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina
  3. 3.Department of Oncology, Zhongshan HospitalFudan UniversityShanghaiChina
  4. 4.Department of Nuclear Medicine, Ren Ji Hospital, School of MedicineShanghai Jiao Tong UniversityShanghaiChina

Personalised recommendations