Skip to main content

Advertisement

SpringerLink
Log in

Ketotherapy as an epigenetic modifier in cancer

  • Published:
Reviews in Endocrine and Metabolic Disorders Aims and scope Submit manuscript

Abstract

Epigenetic alterations in cancer play a variety of roles. Aberrant DNA methylation, as one of the epigenetic mechanisms, has been widely studied in both tumor and liquid biopsies and provide a useful bench mark for treatment response in cancer. Recently, several studies have reported an association between the type of diet and epigenetic modifications. Whereby there is a growing interest in finding the “anti-cancer diet formula”, if such a thing exists. In this sense, ketogenic diets (KD) have reported potentially beneficial effects, which were able to prevent malignancies and decrease tumor growth. Some studies have even shown increased survival in cancer patients, reduced side effects of cytotoxic treatments, and intensified efficacy of cancer therapies. Although the biological mechanisms of KD are not well understood, it has been reported that KD may affect DNA methylation by modulating the expression of crucial genes involved in tumor survival and proliferation. However, there are many considerations to take into account to use ketotherapy in cancer, such as epigenetic mark, type of cancer, immunological and metabolic state or microbiota profile. In this review, we argue about ketotherapy as a potential strategy to consider as coadjuvant of cancer therapy. We will focus on mainly epigenetic mechanisms and dietary approach that could be included in the current clinical practice guidelines.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Cazaly E, Saad J, Wang W, Heckman C, Ollikainen M, Tang J. Making sense of the epigenome using data integration approaches. Front Pharmacol. 2019. https://doi.org/10.3389/fphar.2019.00126.

  2. Jankowska AM, Millward CL, Caldwell CW. The potential of DNA modifications as biomarkers and therapeutic targets in oncology. Expert Rev Mol Diagn. 2015;15:1325–37. https://doi.org/10.1586/14737159.2015.1084229.

    Article  CAS  PubMed  Google Scholar 

  3. Herman JG. Hypermethylation of tumor suppressor genes in cancer. Semin Cancer Biol. 1999. https://doi.org/10.1006/scbi.1999.0138.

  4. Noberini R, et al. Profiling of epigenetic features in clinical samples reveals novel widespread changes in cancer. Cancers (Basel). 2019. https://doi.org/10.3390/cancers11050723.

  5. Dumitrescu RG. Early epigenetic markers for precision medicine. Methods Mol Biol. 2018.

  6. Ingenito F, Roscigno G, Affinito A, Nuzzo S, Scognamiglio I, Quintavalle C, et al. The role of Exo-miRNAs in cancer: a focus on therapeutic and diagnostic applications. Int J Mol Sci. 2019;20. https://doi.org/10.3390/ijms20194687.

  7. Lopez-Serra P, Esteller M. DNA methylation-associated silencing of tumor-suppressor microRNAs in cancer. Oncogene. 2012. https://doi.org/10.1038/onc.2011.354.

  8. Mummaneni P, Shord SS. Epigenetics and oncology. Pharmacotherapy. 2014. https://doi.org/10.1002/phar.1408.

  9. Nunes SP, et al. Cell-free DNA methylation of selected genes allows for early detection of the major cancers in women. Cancers (Basel). 2018. https://doi.org/10.3390/cancers10100357.

  10. Chimonidou M, et al. DNA methylation of tumor suppressor and metastasis suppressor genes in circulating tumor cells. Clin Chem. 2011. https://doi.org/10.1373/clinchem.2011.165902.

  11. Brennan CA, Garrett WS. Gut microbiota, inflammation, and colorectal Cancer. Annu Rev Microbiol. 2016. https://doi.org/10.1146/annurev-micro-102215-095513.

  12. Hu XT, He C. Recent progress in the study of methylated tumor suppressor genes in gastric cancer. Chin J Cancer. 2013. https://doi.org/10.5732/cjc.011.10175.

  13. Kondo Y, Issa JPJ. Epigenetic changes in colorectal cancer\. Cancer Metast Rev. 2004. https://doi.org/10.1023/A:1025806911782.

  14. Sakai E, Nakajima A, Kaneda A. Accumulation of aberrant DNA methylation during colorectal cancer development. World J Gastroenterol. 2014. https://doi.org/10.3748/wjg.v20.i4.978.

  15. Kumar A, Gosipatala SB, Pandey A, Singh P. Prognostic relevance of SFRP1 gene promoter methylation in colorectal carcinoma. Asian Pacific J Cancer Prev. 2019. https://doi.org/10.31557/APJCP.2019.20.5.1571.

  16. Tokarz P, Pawlowska E, Bialkowska-Warzecha J, Blasiak J. The significance of DNA methylation profile in metastasis-related genes for the progression of colorectal cancer. Cell Mol Biol. 2017. https://doi.org/10.14715/cmb/2017.63.2.12.

  17. Ayers D, Boughanem H, MacÍas-González M, Weygant N. Epigenetic influences in the obesity/colorectal cancer axis: a novel theragnostic avenue. J Oncol. 2019. https://doi.org/10.1155/2019/7406078.

  18. Sapienza C, Issa J-P. Diet, nutrition, and cancer epigenetics. Annu Rev Nutr. 2016. https://doi.org/10.1146/annurev-nutr-121415-112634.

  19. Jones PA, Issa JPJ, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17:630–41. https://doi.org/10.1038/nrg.2016.93.

    Article  CAS  PubMed  Google Scholar 

  20. Palomeras S, et al. Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer. Breast Cancer Res. 2019. https://doi.org/10.1186/s13058-019-1160-x.

  21. Pineda B, et al. A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients. Clin Epigenetics. 2019. https://doi.org/10.1186/s13148-019-0626-0.

  22. Diaz-Lagares A, Crujeiras AB, Lopez-Serra P, Soler M, Setien F, Goyal A, et al. Epigenetic inactivation of the p53-induced long noncoding RNA TP53 target 1 in human cancer. Proc Natl Acad Sci U S A. 2016;113:E7535–44. https://doi.org/10.1073/pnas.1608585113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Costa-Pinheiro P, Montezuma D, Henrique R, Jerónimo C. Diagnostic and prognostic epigenetic biomarkers in cancer. Epigenomics. 2015. https://doi.org/10.2217/epi.15.56.

  24. Deng D, Liu Z, Du Y. Epigenetic alterations as cancer diagnostic, prognostic, and predictive biomarkers. Adv Genet. 2010;71:125–76. https://doi.org/10.1016/B978-0-12-380864-6.00005-5.

  25. Pan Y, Liu G, Zhou F, Su B, Li Y. DNA methylation profiles in cancer diagnosis and therapeutics. Clin Exp Med. 2018;18:1–14. https://doi.org/10.1007/s10238-017-0467-0.

    Article  CAS  PubMed  Google Scholar 

  26. Mari-Alexandre J, Diaz-Lagares A, Villalba M, Juan O, Crujeiras AB, Calvo A, et al. Translating cancer epigenomics into the clinic: focus on lung cancer. Transl Res. 2017;189:76–92. https://doi.org/10.1016/j.trsl.2017.05.008.

    Article  CAS  PubMed  Google Scholar 

  27. Esposito A, Criscitiello C, Locatelli M, Milano M, Curigliano G. Liquid biopsies for solid tumors: understanding tumor heterogeneity and real time monitoring of early resistance to targeted therapies. Pharmacol Ther. 2016;157:120–4. https://doi.org/10.1016/j.pharmthera.2015.11.007.

    Article  CAS  PubMed  Google Scholar 

  28. Supic G, Jagodic M, Magic Z. Epigenetics: a new link between nutrition and cancer. Nutr Cancer. 2013;65:781–92. https://doi.org/10.1080/01635581.2013.805794.

    Article  CAS  PubMed  Google Scholar 

  29. Andreescu N, Puiu M, Niculescu M. Effects of dietary nutrients on epigenetic changes in cancer. Methods Mol Biol. 2018.

  30. Wang YP, Lei QY. Metabolic recoding of epigenetics in cancer. Cancer Commun (London, England). 2018. https://doi.org/10.1186/s40880-018-0302-3.

  31. Bishop KS, Ferguson LR. The interaction between epigenetics, nutrition and the development of cancer. Nutrients. 2015. https://doi.org/10.3390/nu7020922.

  32. de B Sampaio LP. Ketogenic diet for epilepsy treatment. Arquivos de Neuro-Psiquiatria. 2016. https://doi.org/10.1590/0004-282X20160116.

  33. Trimboli P, Castellana M, Bellido D, Casanueva FF. Confusion in the nomenclature of ketogenic diets blurs evidence. Rev Endocr Metab Disord. 2020;21:1–3. https://doi.org/10.1007/s11154-020-09546-9.

    Article  PubMed  Google Scholar 

  34. Longo VD, Mattson MP. Fasting: Molecular mechanisms and clinical applications. Cell Metab. 2014. https://doi.org/10.1016/j.cmet.2013.12.008.

  35. Prabhakar A, et al. Acetone as biomarker for ketosis buildup capability - a study in healthy individuals under combined high fat and starvation diets. Nutr J. 2015. https://doi.org/10.1186/s12937-015-0028-x.

  36. Martin-Mcgill KJ, Jackson CF, Bresnahan R, Levy RG, Cooper PN. Ketogenic diets for drug-resistant epilepsy. Cochrane Database Syst Rev. 2018. https://doi.org/10.1002/14651858.CD001903.pub4.

  37. Moreno B, Crujeiras AB, Bellido D, Sajoux I, Casanueva FF. Obesity treatment by very low-calorie-ketogenic diet at two years: reduction in visceral fat and on the burden of disease. Endocrine. 2016.

  38. Johnstone AM, Horgan GW, Murison SD, Bremner DM, Lobley GE. Effects of a high-protein ketogenic diet on hunger, appetite, and weight loss in obese men feeding ad libitum. Am J Clin Nutr. 2008. https://doi.org/10.1093/ajcn/87.1.44.

  39. Mavropoulos JC, Yancy WS, Hepburn J, Westman EC. The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study. Nutr Metab. 2005. https://doi.org/10.1186/1743-7075-2-35.

  40. Allen BG, et al. Ketogenic diets as an adjuvant cancer therapy: History and potential mechanism. Redox Biol. 2014. https://doi.org/10.1016/j.redox.2014.08.002.

  41. Rubini A, et al. Effects of twenty days of the Ketogenic diet on metabolic and respiratory parameters in healthy subjects. Lung. 2015. https://doi.org/10.1007/s00408-015-9806-7.

  42. Castellana M, Conte E, Cignarelli A, Perrini S, Giustina A, Giovanella L, et al. Efficacy and safety of very low calorie ketogenic diet (VLCKD) in patients with overweight and obesity: a systematic review and meta-analysis. Rev Endocr Metab Disord. 2020;21:5–16. https://doi.org/10.1007/s11154-019-09514-y.

    Article  CAS  PubMed  Google Scholar 

  43. Mohorko N, et al. Weight loss, improved physical performance, cognitive function, eating behavior, and metabolic profile in a 12-week ketogenic diet in obese adults. Nutr Res. 2019. https://doi.org/10.1016/j.nutres.2018.11.007.

  44. Gomez-Arbelaez D, et al. Body composition changes after very-low-calorie ketogenic diet in obesity evaluated by 3 standardized methods. J Clin Endocrinol Metab. 2017. https://doi.org/10.1210/jc.2016-2385.

  45. Sajoux I, et al. Effect of a very-low-calorie ketogenic diet on circulating myokine levels compared with the effect of bariatric surgery or a low-calorie diet in patients with obesity. Nutrients. 2019. https://doi.org/10.3390/nu11102368.

  46. Castro AI, et al. Effect of a very low-calorie ketogenic diet on food and alcohol cravings, physical and sexual activity, sleep disturbances, and quality of life in obese patients. Nutrients. 2018. https://doi.org/10.3390/nu10101348.

  47. Schmidt M, Pfetzer N, Schwab M, Strauss I, Kämmerer U. Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: a pilot trial. Nutr Metab. 2011. https://doi.org/10.1186/1743-7075-8-54.

  48. Chung H-Y, Park YK. Rationale, feasibility and acceptability of Ketogenic diet for cancer treatment. J Cancer Prev. 2017. https://doi.org/10.15430/jcp.2017.22.3.127.

  49. Khodadadi S, et al. Tumor cells growth and survival time with the ketogenic diet in animal models: A systematic review. Int J Prev Med. 2017. https://doi.org/10.4103/2008-7802.207035.

  50. O’Flanagan CH, Smith LA, McDonell SB, Hursting SD. When less may be more: calorie restriction and response to cancer therapy. BMC Med. 2017. https://doi.org/10.1186/s12916-017-0873-x.

  51. Brandhorst S, Longo VD. Fasting and caloric restriction in cancer prevention and treatment. Recent Resul Cancer Res. 2016.

  52. Lettieri-Barbato D, Aquilano K. Pushing the limits of cancer therapy: the nutrient game. Front Oncol. 2018. https://doi.org/10.3389/fonc.2018.00148.

  53. Trepanowski JF, Canale RE, Marshall KE, Kabir MM, Bloomer RJ. Impact of caloric and dietary restriction regimens on markers of health and longevity in humans and animals: a summary of available findings. Nutr J. 2011. https://doi.org/10.1186/1475-2891-10-107.

  54. Khandekar MJ, Cohen P, Spiegelman BM. Molecular mechanisms of cancer development in obesity. Nat Rev Cancer. 2011;11(12):886–95. https://doi.org/10.1038/nrc3174.

    Article  CAS  PubMed  Google Scholar 

  55. Stone TW, McPherson M, Gail Darlington L. Obesity and cancer: existing and new hypotheses for a causal connection. EBioMedicine. 2018. https://doi.org/10.1016/j.ebiom.2018.02.022.

  56. Cignarelli A, Genchi VA, Caruso I, Natalicchio A, Perrini S, Laviola L, et al. Diabetes and cancer: Pathophysiological fundamentals of a ‘dangerous affair. Diabetes Res Clin Pract. 2018;143:378–88. https://doi.org/10.1016/j.diabres.2018.04.002.

    Article  PubMed  Google Scholar 

  57. Weber DD, Aminazdeh-Gohari S, Kofler B. Ketogenic diet in cancer therapy. Aging. 2018. https://doi.org/10.18632/aging.101382.

  58. Spinelli E, Blackford R. Gut microbiota, the Ketogenic diet and epilepsy. Pediatr Neurol Briefs. 2018. https://doi.org/10.15844/pedneurbriefs-32-10.

  59. Goldberg EL, Shchukina I, Asher JL, Sidorov S, Artyomov MN, Dixit VD. Ketogenesis activates metabolically protective γδ T cells in visceral adipose tissue. Nat Metab. 2020. https://doi.org/10.1038/s42255-019-0160-6.

  60. Boison D. New insights into the mechanisms of the ketogenic diet. Curr Opin Neuro. 2017. https://doi.org/10.1097/WCO.0000000000000432.

  61. Shimazu T, et al. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science (80-. ). 2013. https://doi.org/10.1126/science.1227166.

  62. Benjamina JS, et al. A ketogenic diet rescues hippocampal memory defects in a mouse model of kabuki syndrome. Proc Natl Acad Sci U S A. 2017;114:125–30. https://doi.org/10.1073/pnas.1611431114.

    Article  CAS  Google Scholar 

  63. Shirahata M, Tang WY, Kostuk EW. A short-term fasting in neonates induces breathing instability and epigenetic modification in the carotid body. Adv Exp Med Biol. 2015. https://doi.org/10.1007/978-3-319-18440-1_20.

  64. Jaworski DM, Namboodiri AMA, Moffett JR. Acetate as a metabolic and epigenetic modifier of cancer therapy. J Cell Biochem. 2016. https://doi.org/10.1002/jcb.25305.

  65. Kinnaird A, Zhao S, Wellen KE, Michelakis ED. Metabolic control of epigenetics in cancer. Nat Rev Cancer. 2016;16:694–707. https://doi.org/10.1038/nrc.2016.82.

    Article  CAS  PubMed  Google Scholar 

  66. Preston MJ, et al. OP16. The KETOGENIC diet induces epigenetic changes that play key roles in tumour development. Neuro Oncol. 2017. https://doi.org/10.1093/neuonc/now292.015.

  67. Hirata E, Sahai E. Tumor microenvironment and differential responses to therapy. Cold Spring Harb Perspect Med. 2017. https://doi.org/10.1101/cshperspect.a026781.

  68. Wu T, Dai Y. Tumor microenvironment and therapeutic response. Cancer Lett. 2017. https://doi.org/10.1016/j.canlet.2016.01.043.

  69. Zielske SP. Epigenetic dna methylation in radiation biology: on the field or on the sidelines? J Cell Biochem. 2015. https://doi.org/10.1002/jcb.24959.

  70. Biswas S, Rao CM. Epigenetics in cancer: fundamentals and beyond. Pharmacol Ther. 2017;173:118–34. https://doi.org/10.1016/j.pharmthera.2017.02.011.

    Article  CAS  PubMed  Google Scholar 

  71. Song SH, Han SW, Bang YJ. Epigenetic-based therapies in cancer: progress to date. Drugs. 2011. https://doi.org/10.2165/11596690-000000000-00000.

  72. Roberti A, Valdes AF, Torrecillas R, Fraga MF, Fernandez AF. Epigenetics in cancer therapy and nanomedicine. Clin Epigenetics. 2019. https://doi.org/10.1186/s13148-019-0675-4.

  73. Smits KM, Melotte V, Niessen HEC, Dubois L, Oberije C, Troost EGC, et al. Epigenetics in radiotherapy: where are we heading? Radiother Oncol. 2014;111:168–77. https://doi.org/10.1016/j.radonc.2014.05.001.

    Article  PubMed  Google Scholar 

  74. Kejík Z, et al. Epigenetic agents in combined anticancer therapy. Future Med Chem. 2018. https://doi.org/10.4155/fmc-2017-0203.

  75. Lakshmaiah KC, Jacob LA, Aparna S, Lokanatha D, Saldanha SC. Epigenetic therapy of cancer with histone deacetylase inhibitors. Ther: J Canc Res; 2014. https://doi.org/10.4103/0973-1482.137937.

    Book  Google Scholar 

  76. Davis S, Mirick DK. Circadian disruption, shift work and the risk of cancer: a summary of the evidence and studies in Seattle. Cancer Causes and Control. 2006. https://doi.org/10.1007/s10552-005-9010-9.

  77. Wendeu-Foyet MG, Menegaux F. Circadian disruption and prostate cancer risk: an updated review of epidemiological evidences. Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2017. https://doi.org/10.1158/1055-9965.EPI-16-1030.

  78. Samuelsson LB, Bovbjerg DH, Roecklein KA, Hall MH. Sleep and circadian disruption and incident breast cancer risk: an evidence-based and theoretical review. Neurosci Biobehav Rev. 2018;84:35–48. https://doi.org/10.1016/j.neubiorev.2017.10.011.

    Article  PubMed  Google Scholar 

  79. Kaczmarek JL, Thompson SV, Holscher HD. Complex interactions of circadian rhythms, eating behaviors, and the gastrointestinal microbiota and their potential impact on health. Nutr Rev. 2017. https://doi.org/10.1093/nutrit/nux036.

  80. Qureshi IA, Mehler MF. Epigenetics of sleep and chronobiology. Curr Neurol Neurosci Rep. 2014;14:432. https://doi.org/10.1007/s11910-013-0432-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Micó V, Díez-Ricote L, Daimiel L. Nutrigenetics and nutrimiromics of the circadian system: the time for human health. Int J Mol Sci. 2016;17. https://doi.org/10.3390/ijms17030299.

  82. Tognini P, et al. Distinct circadian signatures in liver and gut clocks revealed by Ketogenic diet. Cell Metab. 2017. https://doi.org/10.1016/j.cmet.2017.08.015.

  83. Manoogian ENC, Panda S. Circadian rhythms, time-restricted feeding, and healthy aging. Ageing Res Rev. 2017;39:59–67. https://doi.org/10.1016/j.arr.2016.12.006.

    Article  PubMed  Google Scholar 

  84. Block KI. The circadian system and cancer: it’s about time! Integr Cancer Ther. 2018;17:3–4. https://doi.org/10.1177/1534735418755916.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Potter GDM, Cade JE, Grant PJ, Hardie LJ. Nutrition and the circadian system. Br J Nutr. 2016. https://doi.org/10.1017/S0007114516002117.

  86. Klement RJ. The emerging role of ketogenic diets in cancer treatment. Curr Opin Clin Nutr Metab Care. 2019;22:129–34. https://doi.org/10.1097/MCO.0000000000000540.

    Article  PubMed  Google Scholar 

  87. Sremanakova J, Sowerbutts AM, Burden S. A systematic review of the use of ketogenic diets in adult patients with cancer. J Hum Nutr Diet. 2018;31:793–802. https://doi.org/10.1111/jhn.12587.

    Article  CAS  PubMed  Google Scholar 

  88. Olson CA, Vuong HE, Yano JM, Liang QY, Nusbaum DJ, Hsiao EY. The gut microbiota mediates the anti-seizure effects of the Ketogenic diet. Cell. 2018. https://doi.org/10.1016/j.cell.2018.04.027.

  89. Vipperla K, O’Keefe SJ. Diet, microbiota, and dysbiosis: a ‘recipe’ for colorectal cancer. Food Function. 2016. https://doi.org/10.1039/c5fo01276g.

  90. Cenit MC, Sanz Y, Codoñer-Franch P. Influence of gut microbiota on neuropsychiatric disorders. World J Gastroenterol. 2017;23:5486–98. https://doi.org/10.3748/wjg.v23.i30.5486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Conlon MA, Bird AR. The impact of diet and lifestyle on gut microbiota and human health. Nutrients. 2015. https://doi.org/10.3390/nu7010017.

  92. Fraumene C, et al. Caloric restriction promotes rapid expansion and long-lasting increase of Lactobacillus in the rat fecal microbiota. Gut Microbes. 2018. https://doi.org/10.1080/19490976.2017.1371894.

  93. Quigley EMM. Microbiota-brain-gut axis and neurodegenerative diseases. Curr Neurol Neurosci Rep. 2017;17. https://doi.org/10.1007/s11910-017-0802-6.

  94. Klement RJ, Pazienza V. Impact of different types of diet on gut microbiota profiles and cancer prevention and treatment. Medicina (B. Aires). 2019. https://doi.org/10.3390/medicina55040084.

  95. Bultman SJ. Interplay between diet, gut microbiota, epigenetic events, and colorectal cancer. Mol Nutr Food Res. 2017;61. https://doi.org/10.1002/mnfr.201500902.

  96. Gutiérrez-Repiso C, et al. Effect of Synbiotic supplementation in a very-low-calorie Ketogenic diet on weight loss achievement and gut microbiota: a randomized controlled pilot study. Mol Nutr Food Res. 2019. https://doi.org/10.1002/mnfr.201900167.

  97. Cabrera-Mulero A, Tinahones A, Bandera B, Moreno-Indias I, Macías-González M, Tinahones FJ. Keto microbiota: a powerful contributor to host disease recovery. Rev Endocr Metab Disord. 2019;20:415–25. https://doi.org/10.1007/s11154-019-09518-8.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Hampton T. Gut microbes may account for the anti-seizure effects of the Ketogenic diet. JAMA-J Am Med Assoc. 2018. https://doi.org/10.1001/jama.2017.12865.

  99. Gopalakrishnan V, Helmink BA, Spencer CN, Reuben A, Wargo JA. The influence of the gut microbiome on cancer, immunity, and cancer immunotherapy. Cancer Cell. 2018. https://doi.org/10.1016/j.ccell.2018.03.015.

  100. Ferris RL. Immunology and immunotherapy of head and neck cancer. J Clin Oncol. 2015;33:3293–304. https://doi.org/10.1200/JCO.2015.61.1509.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Nishida N, Kudo M. Oncogenic signal and tumor microenvironment in hepatocellular carcinoma. Oncology (Switzerland). 2017. https://doi.org/10.1159/000481246.

  102. Däbritz J, Menheniott TR. Linking immunity, epigenetics, and cancer in inflammatory bowel disease. Inflamm Bowel Dis. 2014;20:1638–54. https://doi.org/10.1097/MIB.0000000000000063.

    Article  PubMed  Google Scholar 

  103. Stakheyeva M, et al. Integral characteristic of the immune system state predicts breast cancer outcome. Exp Oncol. 2019. https://doi.org/10.32471/exp-oncology.2312-8852.vol-41-no-1.12593.

  104. Wright C, Simone NL. Obesity and tumor growth: inflammation, immunity, and the role of a ketogenic diet. Curr Opin Clin Nutr Metab Care. 2016;19:294–9. https://doi.org/10.1097/MCO.0000000000000286.

    Article  CAS  PubMed  Google Scholar 

  105. Elashi AA, Sasidharan Nair V, Taha RZ, Shaath H, Elkord E. DNA methylation of immune checkpoints in the peripheral blood of breast and colorectal cancer patients. Oncoimmunology. 2019. https://doi.org/10.1080/2162402X.2018.1542918.

  106. Himbert C, Delphan M, Scherer D, Bowers LW, Hursting S, Ulrich CM. Signals from the adipose microenvironment and the obesity-cancer link-a systematic review. Cancer Prev Res. 2017. https://doi.org/10.1158/1940-6207.CAPR-16-0322.

  107. Hursting SD, et al. Reducing the weight of cancer: mechanistic targets for breaking the obesity-carcinogenesis link. Best Pract Res Clin Endocrinol Metab. 2008. https://doi.org/10.1016/j.beem.2008.08.009.

  108. Crujeiras AB, et al. Secreted factors derived from obese visceral adipose tissue regulate the expression of breast malignant transformation genes. Int J Obes. 2016. https://doi.org/10.1038/ijo.2015.208.

  109. Cabia B, Andrade S, Carreira MC, Casanueva FF, Crujeiras AB. A role for novel adipose tissue-secreted factors in obesity-related carcinogenesis. Obes Rev. 2016. https://doi.org/10.1111/obr.12377.

  110. Crujeiras AB, Casanueva FF. Obesity and the reproductive system disorders: epigenetics as a potential bridge. Hum Reprod Update. 2015;21:249–61. https://doi.org/10.1093/humupd/dmu060.

    Article  CAS  PubMed  Google Scholar 

  111. Berger NA, Scacheri PC. Targeting epigenetics to prevent obesity promoted cancers. Cancer Prev Res. 2018. https://doi.org/10.1158/1940-6207.CAPR-18-0043.

  112. Dong L, Ma L, Ma GH, Ren H. Genome-wide analysis reveals DNA methylation alterations in obesity associated with high risk of colorectal cancer. Sci Rep. 2019. https://doi.org/10.1038/s41598-019-41616-0.

  113. Crujeiras AB, Diaz-Lagares A, Stefansson OA, Macias-Gonzalez M, Sandoval J, Cueva J, et al. Obesity and menopause modify the epigenomic profile of breast cancer. Endocr Relat Cancer. 2017;24:351–63. https://doi.org/10.1530/ERC-16-0565.

    Article  CAS  PubMed  Google Scholar 

  114. Crujeiras AB, et al. Identification of an episignature of human colorectal cancer associated with obesity by genome-wide DNA methylation analysis. Int J Obes. 2018. https://doi.org/10.1038/s41366-018-0065-6.

  115. Castellano-Castillo D, et al. Adipose tissue inflammation and VDR expression and methylation in colorectal cancer. Clin Epigenetics. 2018. https://doi.org/10.1186/s13148-018-0493-0.

  116. Cabrera-Mulero A, et al. Novel SFRP2 DNA methylation profile following neoadjuvant therapy in colorectal cancer patients with different grades of BMI. J Clin Med. 2019;8(7). https://doi.org/10.3390/jcm8071041.

  117. Izquierdo AG, et al. An energy restriction-based weight loss intervention is able to reverse the effects of obesity on the expression of liver tumor-promoting genes. FASEB J. 2020. https://doi.org/10.1096/fj.201901147RR.

  118. Bultman SJ. A reversible epigenetic link between obesity and cancer risk. Trends Endocrinol Metab. 2018;29:529–31. https://doi.org/10.1016/j.tem.2018.05.004.

    Article  CAS  PubMed  Google Scholar 

  119. Gomez-Arbelaez D, et al. Resting metabolic rate of obese patients under very low calorie ketogenic diet. Nutr Metab. 2018. https://doi.org/10.1186/s12986-018-0249-z.

  120. Crujeiras AB, et al. Plasma FGF21 levels in obese patients undergoing energy-restricted diets or bariatric surgery: a marker of metabolic stress? Int J Obes. 2017. https://doi.org/10.1038/ijo.2017.138.

  121. Gomez-Arbelaez D, et al. Acid–base safety during the course of a very low-calorie-ketogenic diet. Endocrine. 2017. https://doi.org/10.1007/s12020-017-1405-3.

  122. Albanese A, Prevedello L, Markovich M, Busetto L, Vettor R, Foletto M. Pre-operative very low calorie Ketogenic diet (VLCKD) vs. very low calorie diet (VLCD): surgical impact. Obes Surg. 2019;29(1):292–6. https://doi.org/10.1007/s11695-018-3523-2.

    Article  PubMed  Google Scholar 

Download references

Funding

This study was supported by “Centros de Investigación En Red” (CIBER, CB06/03/0018) of the “Instituto de Salud Carlos III” (ISCIII) and grants from ISCIII (PI18/01399 and PI18/01160), and co-financed by the European Regional Development Fund (FEDER). ABC is funded by a research contract “Miguel Servet” (CP17/00088) from the ISCIII, and co-financed by the European Regional Development Fund (FEDER). MMG was the recipient of the Nicolas Monardes Programme from the “Servicio Andaluz de Salud, Junta de Andalucia”, Spain (RC-0001-2018 and C-0029-2023).

Author information

Authors and Affiliations

  1. Department of Endocrinology and Nutrition, Virgen de la Victoria University Hospital, University of Malaga (IBIMA), 29010, Málaga, Spain

    Borja Bandera-Merchan, Manuel Macias-Gonzalez & Francisco J. Tinahones

  2. Biomedical Research Institute of Malaga (IBIMA). Faculty of Science, University of Malaga, 29010, Málaga, Spain

    Hatim Boughanem

  3. Epigenomics in Endocrinology and Nutrition Group, Instituto de Investigación Sanitaria (IDIS), Complejo Hospitalario Universitario de Santiago (CHUS/SERGAS), 15706, Santiago de Compostela, Spain

    Ana B. Crujeiras

  4. CIBEROBN (CIBER in Physiopathology of Obesity and Nutrition), Instituto de Salud Carlos III, 28029, Madrid, Spain

    Ana B. Crujeiras, Manuel Macias-Gonzalez & Francisco J. Tinahones

Authors
  1. Borja Bandera-Merchan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hatim Boughanem
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ana B. Crujeiras
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manuel Macias-Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Francisco J. Tinahones
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

BBM, FJT and MMG contributed conception and design of the manuscript; HB and ABC organized the literature. BBM wrote the first draft of the manuscript; BBM and HB contribute to figures design. All authors contributed to manuscript revision, read and approved the submitted version.

Corresponding author

Correspondence to Manuel Macias-Gonzalez.

Ethics declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bandera-Merchan, B., Boughanem, H., Crujeiras, A.B. et al. Ketotherapy as an epigenetic modifier in cancer. Rev Endocr Metab Disord 21, 509–519 (2020). https://doi.org/10.1007/s11154-020-09567-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11154-020-09567-4

Keywords

Search

Navigation