cycle progression. Dysregulation of ACLY and PDC contributes to metabolic reprogramming and promotes the development of multiple cancers. At the same time, glucose metabolism maintains the NAD+/NADH ratio, and NAD+ participates in SIRT-mediated histone deacetylation. SIRT enzyme activity is altered in various malignancies, and inhibiting SIRT6, a histone deacetylase that acts on acetylated H3K9 and H3K56, promotes tumorigenesis. SIRT7, which deacetylates H3K18 and thereby represses transcription of target genes, is activated in cancer to stabilize cells in the transformed state. Nutrients appear to modulate SIRT activity. For example, long-chain fatty acids activate the deacetylase function of SIRT6, and this may affect histone acetylation. Addiction Epigenetic modifications of histone tails in specific regions of the brain are of central importance in addictions, and much of the work on addiction has focused on histone acetylation. Once particular epigenetic alterations occur, they appear to be long lasting "molecular scars" that may account for the persistence of addictions. Cigarette smokers (about 21% of the US population) are usually addicted to nicotine. After 7 days of nicotine treatment of mice, acetylation of both histone H3 and histone H4 was increased at the FosB promoter in the nucleus accumbens of the brain, causing 61% increase in FosB expression. This would also increase expression of the splice variant Delta FosB. In the nucleus accumbens of the brain, Delta FosB functions as a "sustained molecular switch" and "master control protein" in the development of an addiction. About 7% of the US population is addicted to alcohol. In rats exposed to alcohol for up to 5 days, there was an increase in histone 3 lysine 9 acetylation in the pronociceptin promoter in the brain amygdala complex. This acetylation is an activating mark for pronociceptin. The nociceptin/nociceptin opioid receptor system is involved in the reinforcing or conditioning effects of alcohol. Cocaine addiction occurs in about 0.5% of the US population. Repeated cocaine administration in mice induces hyperacetylation of histone 3 (H3) or histone 4 (H4) at 1,696 genes in one brain "reward" region [the nucleus accumbens (NAc)] and deacetylation at 206 genes. At least 45 genes, shown in previous studies to be upregulated in the NAc of mice after chronic cocaine exposure, were found to be associated with hyperacetylation of H3 or H4. Many of these individual genes are directly related to aspects of addiction associated with cocaine exposure. In rodent models, many agents causing addiction, including tobacco smoke products,