Pancreatic cancer is characterized by poor overall survival and few efficacious therapeutic interventions. One area that has offered significant scope for further exploration are the numerous metabolic disturbances in preclinical models of pancreatic cancer.
Given the relative hypoxia of the tumor microenvironment and the limited nutrient availability, pancreatic tumor cells undergo substantial metabolic rewiring. Several of these derangements lead to imbalances in metabolites, including S-adenosylmethionine (SAM), α-ketoglutarate (αKG), and acetyl-CoA that are crucial to the regulation of epigenetic landscapes. They are substrate (SAM, acetyl-CoA) or substrates (αKG) for enzymes that modify chromatin conformation and regulate gene expression. In particular, we demonstrated that the availability of acetyl-CoA influences histone acetyl-transferase (HATs) activity, dictates global levels of histone acetylation.
Of note, oncogenes actively reprogram both cell metabolism and epigenetics. Previously, we have demonstrated that pancreatic cancer initiation features abundant epigenetic reprogramming in the progression to neoplasia, and that the cytoplasmic enzyme ATP-citrate lyase (ACLY), which produces acetyl-CoA from citrate, is essential to the neoplastic process. In mouse models, Acly deletion diminishes the enhancement of histone acetylation that occurs in response to mutant KRAS.
