Review: Ketogenic diet in the treatment of cancer – Where do we stand? 評論：生酮飲食治療癌症-我們的立場是什麼？

4.6. Ketogenic diet regulates gene expression

A variety of studies showed that KDs modulate gene expression. Gene expression profiling studies in glioma indicate that KDs can reverse the patterns of gene expression in tumors to those of non-tumor cells [161], [162]. The normalization of gene expression by the KD could be a result of the elevated levels of ketone bodies produced under the diet. In the kidneys of aged rats, BHB reduced aging-related inflammation through upregulation of forkhead transcription factor 1 and its target genes [160].

In addition, BHB has been shown to inhibit histone deacetylases (HDACs) [163], [164], [165]. HDACs are enzymes that remove acetyl groups from lysine residues on histones and other proteins such as transcription factors and enzymes. Deacetylation of histones loosens the tight wrapping of DNA, thus enabling gene transcription, whereas deacetylation of transcription factors or enzymes can increase or decrease their activity. Shimazu et al. found that BHB inhibits HDAC1, HDAC3, and HDAC4, supporting the physiological relevance of this mechanism of action [163]. HDACs are involved in multiple different stages of cancer. Aberrant expression of classic HDACs has been linked to a variety of malignancies, including solid and hematological tumors. In most cases, a high level of HDACs is associated with advanced disease and poor outcomes in patients [166]. It was shown that a KD increases overall lysine acetylation levels as well as acetylation of p53, the most frequently affected tumor suppressor in cancer. The authors hypothesized that p53 hyperacetylation and stabilization may also have contributed to the marked decrease in cancer incidence in the mice fed a KD for a long period [167]. Interestingly, posttranslational modification of histones via lysine β-hydroxybutyrylation has been reported recently [168]. Histone β-hydroxybutyrylation thus represents a new epigenetic regulatory mark that couples metabolism to gene expression. However, Chriett et al. were not able to confirm the inhibitory effect of BHB on HDACs, either in vivo or in vitro. They reported that butyrate, a short chain fatty acid structurally similar to BHB, is a strong inhibitor of HDACs, which resulted in an anti-inflammatory effect [164].

The KD also affects DNA methylation [169]. However, it is likely that ketone bodies or KDs influence the global levels of many more posttranslational modifications than reported so far. It was estimated that over 200 different posttranslational modifications exist, and identification of the specific targets might open a new frontier in fighting a variety of diseases, including cancer.
4.7. Ketogenic diet and ROS production

Reprograming of metabolism in cancer cells, mitochondrial dysfunction, and microenvironment-associated instability all induce continuous and elevated production of reactive oxygen species (ROS), which, in turn, promote tumor progression and resistance to therapies [170]. The antioxidant glutathione and the transcription factor Nrf2 contribute in balancing ROS levels [170]. As shown in preclinical rat studies, the KD increased the level of glutathione and activated the Nrf2 detoxification pathway [171], [172]. Moreover, in a glioma mouse model, the KD induced antitumor effects and decreased the production of ROS in tumor cells by altering the expression of genes involved in modulating ROS levels and oxidative stress [161], [162].

In contrast, it has been hypothesized that increased ROS production of cancer cells may be compensated by the generation of reducing equivalents through elevated glycolysis and pentose phosphate pathway activity [173]. Thus, limiting the availability of glucose by the KD could selectively induce metabolic oxidative stress in cancer cells. In line with this hypothesis, the combination of a KD and radiation therapy increased the level of oxidative stress and reduced tumor growth in lung and pancreatic cancer-bearing mice [53], [55]. Targeting cancer cells by radiotherapy leads to cellular stress mediated by ROS. However, tumor areas with a lack or low amounts of oxygen are more resistant to radiotherapy than well-oxygenated tumors [174]. Thus, the ROS inducing potential of the KD may explain its additive effects on radiotherapy [53].

Finally, the antitumor effect of the KD has been associated with both increased and reduced ROS levels, indicating that the KD potentially interferes with the tumorigenic ROS balance of cancer cells [175].