Oncogene-induced metabolic reprogramming alters global histone acetylation during tumorigenesis.
Major finding: Oncogene-induced metabolic reprogramming alters global histone acetylation during tumorigenesis.
Mechanism: AKT regulates acetyl-CoA production by promoting glucose metabolism and activation of ACLY.
Impact: Therapy directed against metabolic targets may reverse epigenetic deregulation in cancer.
Metabolic rewiring has recently been established as a hallmark of cancer cells and is driven by increased oncogene activity and decreased tumor suppressor activity. Changes in specific metabolic enzymes, such as ATP-citrate lyase (ACLY), alter the activity of chromatin-modifying enzymes in cancer cells, but whether tumor metabolism contributes to broader alterations in the epigenetic landscape remains unclear. Lee, Carrer, Shah, and colleagues found that histone acetylation levels were correlated with glucose availability in several cancer cell lines and that, when deprived of glucose, these cells failed to maintain high acetyl-histone levels. The histone acetyltransferase substrate acetyl-CoA induced the expression of proliferation-related genes and was dynamically regulated with varying glucose levels in glioblastoma cells. Low glucose conditions resulted in decreased acetyl-CoA and elevated levels of reduced CoA (CoASH), and the nuclear ratio of acetyl-CoA and CoASH modulated histone acetylation. Activation of the KrasG12D oncogene in a mouse model of pancreatic cancer increased global histone acetylation prior to tumor formation. Histone acetylation was increased in premalignant and cancer cells as a result of AKT activation, which enhanced glucose uptake and promoted acetyl-CoA production via phosphorylation of ACLY, whereas inhibition of the AKT pathway significantly reduced glucose consumption and histone acetylation in vitro. In addition, expression of constitutively activated AKT allowed for sustained histone acetylation in glucose-limited conditions and acutely promoted histone acetylation in vivo. Furthermore, phosphorylated AKT was correlated with histone acetylation levels in established human tumors, and low histone acetylation levels were associated with therapeutic failure in prostate cancer. These data suggest that oncogene-induced metabolic reprogramming drives changes in the epigenome of cancer cells, which can in turn influence disease progression. Moreover, these findings establish a rationale for pursuing metabolic targets as a means to pharmacologically reverse epigenetic deregulation in cancer.
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