The ACSS2-PPARD-BCAT1 axis synchronously regulates branched-chain amino acid metabolism and development in pancreatic cancer.

The characteristics of the tumor microenvironment (TME) of pancreatic cancer include an abundant stroma, hypoxia, insufficient blood supply and high degree of immunosuppression. Therefore, overcoming the TME conditions to reach a hypermetabolic state is a concern for the treatment of pancreatic cancer. Previous studies have demonstrated that tumor cells adapt to the TME by activating or increasing the expression level of ACSS2 under metabolic stress. Our study focuses mainly on the relationship between ACSS2 and amino acid metabolism. We find that ACSS2 is generally highly expressed and promotes the proliferation and invasiveness of pancreatic cancer. Knockout of ACSS2 reduces the catabolism of branched chain amino acids (BCAAs) by inhibiting the transcription of BCAT1. ACSS2 participates in the regulation of histone and transcription factor acetylation. Mechanistically, ACSS2 promotes acetylation at the H3K27 site in the PPARD promoter region to increase the transcription of BCAT1 and ultimately alters the metabolic status of BCAAs. Moreover, the proliferation and invasion status induced by ACSS2 can be partly reversed by BCAT1 in pancreatic cancer cells. In summary, we believe that targeting the ACSS2-PPARD-BCAT1 axis has certain clinical value and can provide a new therapeutic strategy for the comprehensive treatment of pancreatic cancer.