腫瘤的發生已知與異常DNA甲基化情形與失調的脂質合成有關，然而彼此之間如何互相影響的調控機制還不是很清楚。另一方面，被廣泛認知為偵測細胞能量的蛋白激酶AMPK近幾年已經被視為一種抑癌因子，先前研究已經指出在癌細胞中活化AMPK可抑制癌細胞的增生。本研究顯示藉由metformin及AICAR活化AMPK會導致TDG啟動子甲基化程度上升，進而使得TDG的表現量下降，隨後降低調控脂質合成基因轉錄因子SREBP1的啟動子去甲基化程度，造成SREBP1的表現量下降而減少癌細胞中脂質的合成，同時抑制癌細胞生長。另外，根據染色質免疫沉澱及DNA沉澱實驗結果發現DNMT3A也參與在AMPK訊息傳遞中。因此，由本篇結果可得知在AMPK調控脂質合成基因表現量中，DNA甲基化與去甲基化扮演著重要的角色，日後或許可以針對調控癌細胞中AMPK的活性及DNA甲基化的程度發展出治療癌症或是相關代謝疾病的嶄新療法。

Tumorigenesis has been reported to be associated with aberrant DNA methylation pattern and unregulated lipogenesis, whereas the molecular mechanism interlinked is still unclear. On the other hand, AMP-activated protein kinase (AMPK), a well-known fuel-sensing enzyme, has been regarded as a tumor suppressor for recent decades because of its inhibitory effect on cancer cell growth. Here, we delineate activation of AMPK by metformin and AICAR leads to increase promoter methylation level of thymine DNA glycosylase (TDG), an enzyme playing an important role in DNA demethylation. Subsequently, the reduction of TDG leads to downregulate sterol regulatory element binding protein 1 (SREBP1s), a family of transcription factor controlling lipogenic gene expression, through promoter demethylation, resulting in decreased lipogenesis and cell proliferation in MCF7 cells. In addition, chromatin and DNA immunoprecipitation studies reveal AMPK-mediated TDG and lipogenic gene expression is regulated by DNA methyltransferase 3A (DNMT3A). Thus, DNA methylation and demethylation act vital linkages between AMPK signaling and lipogenesis. Targeting AMPK-mediated DNA methylation may provide a promising means of treating cancer or metabolic diseases.

Abramson, H.N. (2011). The lipogenesis pathway as a cancer target. Journal of Medicinal Chemistry 54, 5615-5638.
Allfrey, V., Faulkner, R., and Mirsky, A. (1964). Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proceedings of the National Academy of Sciences 51, 786-794.
Anisimov, V. N., Berstein, L. M., Popovich, I. G., Zabezhinski, M. A., Egormin, P. A., Piskunova, T. S., Sememchenko, A. V., Tyndyk, M. L., Yurova, M. N., Kovalenko, I. G. & Poroshina, T. E. (2011). If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY) 3, 148-57.
Ateeq, B., Unterberger, A., Szyf, M., and Rabbani, S.A. (2008). Pharmacological inhibition of DNA methylation induces proinvasive and prometastatic genes in vitro and in vivo. Neoplasia 10, 266-278.
Baenke, F., Peck, B., Miess, H., and Schulze, A. (2013). Hooked on fat: the role of lipid synthesis in cancer metabolism and tumour development. Disease Models & Mechanisms 6, 1353-1363.
Bannister, A.J., and Kouzarides, T. (2011). Regulation of chromatin by histone modifications. Cell Research 21, 381-395.
Bogdanović, O., and Veenstra, G.J.C. (2009). DNA methylation and methyl-CpG binding proteins: developmental requirements and function. Chromosoma 118, 549-565.
Boyes, J., and Bird, A. (1991). DNA methylation inhibits transcription indirectly via a methyl-CpG binding protein. Cell 64, 1123-1134.
Bungard, D., Fuerth, B.J., Zeng, P.-Y., Faubert, B., Maas, N.L., Viollet, B., Carling, D., Thompson, C.B., Jones, R.G., and Berger, S.L. (2010). Signaling kinase AMPK activates stress-promoted transcription via histone H2B phosphorylation. Science 329, 1201-1205.
Carling, D., Thornton, C., Woods, A., and Sanders, M.J. (2012). AMP-activated protein kinase: new regulation, new roles? Biochemical Journal 445, 11-27.
Carpenter, B., Hill, K.J., Charalambous, M., Wagner, K.J., Lahiri, D., James, D.I., Andersen, J.S., Schumacher, V., Royer-Pokora, B., and Mann, M. (2004). BASP1 is a transcriptional cosuppressor for the Wilms' tumor suppressor protein WT1. Molecular and Cellular Biology 24, 537-549.
Chajès, V., Cambot, M., Moreau, K., Lenoir, G.M., and Joulin, V. (2006). Acetyl-CoA carboxylase α is essential to breast cancer cell survival. Cancer Research 66, 5287-5294.
Chakrabarti, P., English, T., Shi, J., Smas, C.M., and Kandror, K.V. (2010). The mTOR complex 1 suppresses lipolysis, stimulates lipogenesis and promotes fat storage. Diabetes 59, 775-781.
Cheah, M.S., Wallace, C.D., and Hoffman, R.M. (1984). Hypomethylation of DNA in human cancer cells: a site-specific change in the c-myc oncogene. Journal of the National Cancer Institute 73, 1057-1065.
Cheng, C., Ru, P., Geng, F., Liu, J., Yoo, J.Y., Wu, X., Cheng, X., Euthine, V., Hu, P., Guo, J.Y., et al. (2015). Glucose-Mediated N-glycosylation of SCAP Is Essential for SREBP-1 Activation and Tumor Growth. Cancer Cell 28, 569-581.
Cortellino, S., Xu, J., Sannai, M., Moore, R., Caretti, E., Cigliano, A., Le Coz, M., Devarajan, K., Wessels, A., and Soprano, D. (2011). Thymine DNA glycosylase is essential for active DNA demethylation by linked deamination-base excision repair. Cell 146, 67-79.
Cuyàs, E., Fernández-Arroyo, S., Verdura, S., García, R.Á.-F., Stursa, J., Werner, L., Blanco-González, E., Montes-Bayón, M., Joven, J., and Viollet, B. (2018). Metformin regulates global DNA methylation via mitochondrial one-carbon metabolism. Oncogene 37, 963.
Edwards, P.A., Tabor, D., Kast, H.R., and Venkateswaran, A. (2000). Regulation of gene expression by SREBP and SCAP. Biochimica et Biophysica Acta (BBA)-Molecular and Cell Biology of Lipids 1529, 103-113.
Faubert, B., Boily, G., Izreig, S., Griss, T., Samborska, B., Dong, Z., Dupuy, F., Chambers, C., Fuerth, B.J., and Viollet, B. (2013). AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metabolism 17, 113-124.
Feinberg, A.P., and Vogelstein, B. (1983). Hypomethylation of ras oncogenes in primary human cancers. Biochemical and Biophysical Research Communications 111, 47-54.
Ferre, P., and Foufelle, F. (2007). SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Hormone Research in Paediatrics 68, 72-82.
Guo, D., Hildebrandt, I.J., Prins, R.M., Soto, H., Mazzotta, M.M., Dang, J., Czernin, J., Shyy, J.Y.-J., Watson, A.D., and Phelps, M. (2009). The AMPK agonist AICAR inhibits the growth of EGFRvIII-expressing glioblastomas by inhibiting lipogenesis. Proceedings of the National Academy of Sciences 106, 12932-12937.
Guo, Y., Pakneshan, P., Gladu, J., Slack, A., Szyf, M., and Rabbani, S.A. (2002). Regulation of DNA methylation in human breast cancer: effect on the urokinase-type plasminogen activator gene production and tumor invasion. Journal of Biological Chemistry 277, 41571-41579.
Gupta, S., Kim, S.Y., Artis, S., Molfese, D.L., Schumacher, A., Sweatt, J.D., Paylor, R.E., and Lubin, F.D. (2010). Histone methylation regulates memory formation. Journal of Neuroscience 30, 3589-3599.
Hashimoto, H., Olanrewaju, Y.O., Zheng, Y., Wilson, G.G., Zhang, X., and Cheng, X. (2014). Wilms tumor protein recognizes 5-carboxylcytosine within a specific DNA sequence. Genes & Development 28, 2304-2313.
He, X., Li, C., Ke, R., Luo, L., and Huang, D. (2017). Down-regulation of adenosine monophosphate–activated protein kinase activity: A driver of cancer. Tumor Biology 39, 1010428317697576.
He, Y.-F., Li, B.-Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., and Li, L. (2011). Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303-1307.
Hellerstein, M.K., Schwarz, J.-M., and Neese, R.A. (1996). Regulation of hepatic de novo lipogenesis in humans. Annual Review of Nutrition 16, 523-557.
Henin, N., Vincent, M.-F., Gruber, H., and Van den Berghe, G. (1995). Inhibition of fatty acid and cholesterol synthesis by stimulation of AMP-activated protein kinase. The FASEB Journal 9, 541-546.
Holman, R. R., Paul, S. K., Bethel, M. A., Matthews, D. R., & Neil, H. A. W. (2008). 10-year follow-up of intensive glucose control in type 2 diabetes. New England Journal of Medicine 359, 1577-1589
Horman, S., Vertommen, D., Heath, R., Neumann, D., Mouton, V., Woods, A., Schlattner, U., Wallimann, T., Carling, D., and Hue, L. (2005). Insulin antagonizes ischemia-induced Thr172 phosphorylation of AMP-activated protein kinase α-subunits in heart via hierarchical phosphorylation of Ser485/491. Journal of Biological Chemistry 281, 5335-5340.
Igal, R.A. (2011). Roles of stearoylCoA desaturase-1 in the regulation of cancer cell growth, survival and tumorigenesis. Cancers 3, 2462-2477.
Ishii, S., IIzuka, K., Miller, B.C., and Uyeda, K. (2004). Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. Proceedings of the National Academy of Sciences 101, 15597-15602.
Jiralerspong, S., Palla, S. L., Giordano, S. H., Meric-Bernstam, F., Liedtke, C., Barnett, C. M., Hsu, L., Hung, M. C., Hortobagyi, C. N. & Gonzalez-Angulo, A. M. (2009). Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. Journal of clinical oncology, 27, 3297-3302.
Jones, P.A. (2012). Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nature Reviews Genetics 13, 484-492.
Jones, P.A., and Baylin, S.B. (2002). The fundamental role of epigenetic events in cancer. Nature Reviews Genetics 3, 415-428.
Kim, H., Park, J., Jung, Y., Song, S. H., Han, S. W., Oh, D. Y., Im, S. A., Bang, Y. J. & Kim, T. Y. (2010). DNA methyltransferase 3-like affects promoter methylation of thymine DNA glycosylase independently of DNMT1 and DNMT3B in cancer cells. International Journal of Oncology 36, 1563-1572.
Kohli, R.M., and Zhang, Y. (2013). TET enzymes, TDG and the dynamics of DNA demethylation. Nature 502, 472-479.
Laplante, M., and Sabatini, D.M. (2012). mTOR signaling in growth control and disease. Cell 149, 274-293.
Li, Y., Xu, S., Mihaylova, M.M., Zheng, B., Hou, X., Jiang, B., Park, O., Luo, Z., Lefai, E., Shyy, J.Y., Gao, B., Wierzbicki, M., Verbeuren, T. J., Shaw, R. J., Cohen, R. A. and Zang, M. (2011). AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metabolism 13, 376-388.
Lozano, I., Van der Werf, R., Bietiger, W., Seyfritz, E., Peronet, C., Pinget, M., Jeandidier, N., Maillard, E., Marchioni, E., and Sigrist, S. (2016). High-fructose and high-fat diet-induced disorders in rats: impact on diabetes risk, hepatic and vascular complications. Nutrition & Metabolism 13, 15.
Luo, D., Xiao, H., Dong, J., Li, Y., Feng, G., Cui, M., and Fan, S. (2017a). B7-H3 regulates lipid metabolism of lung cancer through SREBP1-mediated expression of FASN. Biochemical and Biophysical Research Communications 482, 1246-1251.
Luo, J., Hong, Y., Lu, Y., Qiu, S., Chaganty, B.K., Zhang, L., Wang, X., Li, Q., and Fan, Z. (2017b). Acetyl-CoA carboxylase rewires cancer metabolism to allow cancer cells to survive inhibition of the Warburg effect by cetuximab. Cancer Letters 384, 39-49.
Luo, R.X., Postigo, A.A., and Dean, D.C. (1998). Rb interacts with histone deacetylase to repress transcription. Cell 92, 463-473.
Luo, Z., Zang, M., and Guo, W. (2010). AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncology 6, 457-470.
Luyimbazi, D., Akcakanat, A., McAuliffe, P.F., Zhang, L., Singh, G., Gonzalez-Angulo, A.M., Chen, H., Do, K.-A., Zheng, Y., and Hung, M.-C. (2010). Rapamycin regulates stearoyl CoA desaturase 1 expression in breast cancer. Molecular Cancer Therapeutics 9, 2770-2784.
Madden, S.L., Cook, D.M., Morris, J.F., Gashler, A., Sukhatme, V.P., and Rauscher, F.J. (1991). Transcriptional repression mediated by the WT1 Wilms tumor gene product. Science 253, 1550-1553.
Marcinko, K., and Steinberg, G.R. (2014). The role of AMPK in controlling metabolism and mitochondrial biogenesis during exercise. Experimental Physiology 99, 1581-1585.
Marin, T.L., Gongol, B., Zhang, F., Martin, M., Johnson, D.A., Xiao, H., Wang, Y., Subramaniam, S., Chien, S., and Shyy, J.Y.-J. (2017). AMPK promotes mitochondrial biogenesis and function by phosphorylating the epigenetic factors DNMT1, RBBP7, and HAT1. Science Signaling. 10, eaaf7478.
McGee, S.L., Van Denderen, B.J., Howlett, K.F., Mollica, J., Schertzer, J.D., Kemp, B.E., and Hargreaves, M. (2008). AMP-activated protein kinase regulates GLUT4 transcription by phosphorylating histone deacetylase 5. Diabetes 57, 860-867.
Menendez, J.A., and Lupu, R. (2007a). Fatty acid synthase and the lipogenic phenotype in cancer pathogenesis. Nature Reviews Cancer 7, 763-777.
Motoshima, H., Goldstein, B.J., Igata, M., and Araki, E. (2006). AMPK and cell proliferation–AMPK as a therapeutic target for atherosclerosis and cancer. The Journal of Physiology 574, 63-71.
Nelson, M.E., Lahiri, S., Chow, J.D., Byrne, F.L., Hargett, S.R., Breen, D.S., Olzomer, E.M., Wu, L.E., Cooney, G.J., and Turner, N. (2017). Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival. Nature Communications 8, 14689.
Ntambi, J.M., Miyazaki, M., Stoehr, J.P., Lan, H., Kendziorski, C.M., Yandell, B.S., Song, Y., Cohen, P., Friedman, J.M., and Attie, A.D. (2002). Loss of stearoyl–CoA desaturase-1 function protects mice against adiposity. Proceedings of the National Academy of Sciences 99, 11482-11486.
Park, S., Gammon, S., Knippers, J., Paulsen, S., Rubink, D., and Winder, W. (2002). Phosphorylation-activity relationships of AMPK and acetyl-CoA carboxylase in muscle. Journal of Applied Physiology 92, 2475-2482.
Peng, B., Hurt, E.M., Hodge, D.R., Thomas, S.B., and Farrar, W.L. (2006). DNA hypermethylation and partial gene silencing of human thymine-DNA glycosylase in multiple myeloma cell lines. Epigenetics 1, 138-145.
Peng, I.-C., Chen, Z., Sun, W., Li, Y.-S., Marin, T.L., Hsu, P.-H., Su, M.-I., Cui, X., Pan, S., and Lytle, C.Y. (2012). Glucagon regulates ACC activity in adipocytes through the CAMKKβ/AMPK pathway. American Journal of Physiology-Endocrinology and Metabolism 302, 1560-1568.
Rattan, R., Giri, S., Singh, A.K., and Singh, I. (2005). 5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase. Journal of Biological Chemistry 280, 39582-39593.
Razin, A., and Riggs, A.D. (1980). DNA methylation and gene function. Science 210, 604-610.
Rena, G., Pearson, E.R., and Sakamoto, K. (2013). Molecular mechanism of action of metformin: old or new insights? Diabetologia 56, 1898-1906.
Repa, J.J., Liang, G., Ou, J., Bashmakov, Y., Lobaccaro, J.-M.A., Shimomura, I., Shan, B., Brown, M.S., Goldstein, J.L., and Mangelsdorf, D.J. (2000). Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRα and LXRβ. Genes & Development 14, 2819-2830.
Russell III, R.R., Bergeron, R., Shulman, G.I., and Young, L.H. (1999). Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. American Journal of Physiology-Heart and Circulatory Physiology 277, 643-649.
Rysman, E., Brusselmans, K., Scheys, K., Timmermans, L., Derua, R., Munck, S., Van Veldhoven, P.P., Waltregny, D., Daniëls, V.W., and Machiels, J. (2010). De novo lipogenesis protects cancer cells from free radicals and chemotherapeutics by promoting membrane lipid saturation. Cancer Research 70, 8117-8126.
Sahra, I.B., Le Marchand-Brustel, Y., Tanti, J.-F., and Bost, F. (2010). Metformin in cancer therapy: a new perspective for an old antidiabetic drug? Molecular Cancer Therapeutics, 1092-1099.
Salminen, A., Kauppinen, A., and Kaarniranta, K. (2016). AMPK/Snf1 signaling regulates histone acetylation: Impact on gene expression and epigenetic functions. Cellular Signalling 28, 887-895.
Saxonov, S., Berg, P., and Brutlag, D.L. (2006). A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proceedings of the National Academy of Sciences 103, 1412-1417.
Schübeler, D. (2015). Function and information content of DNA methylation. Nature 517, 321.
Sehdev, A., Shih, Y. C. T., Vekhter, B., Bissonnette, M. B., Olopade, O. I., & Polite, B. N. (2015). Metformin for primary colorectal cancer prevention in patients with diabetes: A case‐control study in a US population. Cancer, 121, 1071-1078.
Shi, W., Xiao, D., Wang, L., Dong, L., Yan, Z., Shen, Z., Chen, S., Chen, Y., and Zhao, W. (2012). Therapeutic metformin/AMPK activation blocked lymphoma cell growth via inhibition of mTOR pathway and induction of autophagy. Cell Death & Disease 3, 275.
Shimomura, I., Bashmakov, Y., Ikemoto, S., Horton, J.D., Brown, M.S., and Goldstein, J.L. (1999). Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proceedings of the National Academy of Sciences 96, 13656-13661.
Smith, Z.D., and Meissner, A. (2013). DNA methylation: roles in mammalian development. Nature Reviews Genetics 14, 204.
Struhl, K. (1998). Histone acetylation and transcriptional regulatory mechanisms. Genes & Development 12, 599-606.
Su, Y.-W., Lin, Y.-H., Pai, M.-H., Lo, A.-C., Lee, Y.-C., Fang, I.-C., Lin, J., Hsieh, R.-K., Chang, Y.-F., and Chen, C.-L. (2014). Association between phosphorylated AMP-activated protein kinase and acetyl-CoA carboxylase expression and outcome in patients with squamous cell carcinoma of the head and neck. PloS One 9, 96183.
Svensson, R.U., Parker, S.J., Eichner, L.J., Kolar, M.J., Wallace, M., Brun, S.N., Lombardo, P.S., Van Nostrand, J.L., Hutchins, A., and Vera, L. (2016). Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nature Medicine 22, 1108-1119.
Swinnen, J.V., Brusselmans, K., and Verhoeven, G. (2006). Increased lipogenesis in cancer cells: new players, novel targets. Current Opinion in Clinical Nutrition & Metabolic Care 9, 358-365.
Swinnen, J.V., Van Veldhoven, P.P., Timmermans, L., De Schrijver, E., Brusselmans, K., Vanderhoydonc, F., Van de Sande, T., Heemers, H., Heyns, W., and Verhoeven, G. (2003). Fatty acid synthase drives the synthesis of phospholipids partitioning into detergent-resistant membrane microdomains. Biochemical and Biophysical Research Communications 302, 898-903.
Vander Heiden, M.G., Cantley, L.C., and Thompson, C.B. (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324, 1029-1033.
Vavvas, D., Apazidis, A., Saha, A.K., Gamble, J., Patel, A., Kemp, B.E., Witters, L.A., and Ruderman, N.B. (1997). Contraction-induced changes in acetyl-CoA carboxylase and 5′-AMP-activated kinase in skeletal muscle. Journal of Biological Chemistry 272, 13255-13261.
Wang, Y. W., He, S. J., Feng, X., Cheng, J., Luo, Y. T., Tian, L., & Huang, Q. (2017). Metformin: a review of its potential indications. Drug Design, Development and Therapy, 11, 2421-2429.
Wheldon, L.M., Abakir, A., Ferjentsik, Z., Dudnakova, T., Strohbuecker, S., Christie, D., Dai, N., Guan, S., Foster, J.M., and Corrêa Jr, I.R. (2014). Transient accumulation of 5-carboxylcytosine indicates involvement of active demethylation in lineage specification of neural stem cells. Cell Reports 7, 1353-1361.
Wu, H., and Zhang, Y. (2014). Reversing DNA methylation: mechanisms, genomics, and biological functions. Cell 156, 45-68.
Xu, X., Yu, T., Shi, J., Chen, X., Zhang, W., Lin, T., Liu, Z., Wang, Y., Zeng, Z., and Wang, C. (2014). Thymine DNA glycosylase is a positive regulator of Wnt signaling in colorectal cancer. Journal of Biological Chemistry 289, 8881-8890.
Yamasaki, L. (2004). Role of the RB tumor suppressor in cancer. Signal Transduction in Cancer (Springer), 209-239.
Yamauchi, T., Kamon, J., Minokoshi, Y.a., Ito, Y., Waki, H., Uchida, S., Yamashita, S., Noda, M., Kita, S., and Ueki, K. (2002). Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nature Medicine 8, 1288.
Yan, L., Zhou, J., Gao, Y., Ghazal, S., Lu, L., Bellone, S., Yang, Y., Liu, N., Zhao, X., and Santin, A. (2015). Regulation of tumor cell migration and invasion by the H19/let-7 axis is antagonized by metformin-induced DNA methylation. Oncogene 34, 3076.
Yang, Q., Liang, X., Sun, X., Zhang, L., Fu, X., Rogers, C.J., Berim, A., Zhang, S., Wang, S., and Wang, B. (2016). AMPK/α-ketoglutarate axis dynamically mediates DNA demethylation in the Prdm16 promoter and brown adipogenesis. Cell Metabolism 24, 542-554.
Yang, X., Yan, L., and Davidson, N.E. (2001). DNA methylation in breast cancer. Endocrine-related Cancer 8, 115-127.
Zahra Bathaie, S., Ashrafi, M., Azizian, M., and Tamanoi, F. (2017). Mevalonate pathway and human cancers. Current Molecular Pharmacology 10, 77-85.
Zaytseva, Y.Y., Rychahou, P.G., Gulhati, P., Elliott, V.A., Mustain, W.C., O'Connor, K., Morris, A.J., Sunkara, M., Weiss, H.L., and Lee, E.Y. (2012). Inhibition of fatty acid synthase attenuates CD44-associated signaling and reduces metastasis in colorectal cancer. Cancer Research 72, 1504-1517.
Zheng, L., Yang, W., Wu, F., Wang, C., Yu, L., Tang, L., Qiu, B., Li, Y., Guo, L., and Wu, M. (2013). Prognostic significance of AMPK activation and therapeutic effects of metformin in hepatocellular carcinoma. Clinical cancer research 19, 5372-5380.
Zhong, T., Men, Y., Lu, L., Geng, T., Zhou, J., Mitsuhashi, A., Shozu, M., Maihle, N., Carmichael, G., and Taylor, H. (2016). Metformin alters DNA methylation genome-wide via the H19/SAHH axis. Oncogene 36, 2345-2354.