P5CS deacetylation mediated by SIRT2 facilitates tumor growth by enhancing mitochondrial respiration in hepatocellular carcinoma.

Cancer cells typically exhibit enhanced mitochondrial metabolism to fulfill their energy and biosynthetic demands for growth. The mitochondrial response to fluctuations in cellular energy demand is essential for cellular adaptation and proper organ function. The mitochondrial delta-1-pyrroline-5-carboxylate synthase (P5CS) encoded by the ALDH18A1 gene, the key enzyme for proline synthesis, is frequently up-regulated during tumor development. However, the regulatory mechanisms governing P5CS activity in the occurrence and development of hepatocellular carcinoma (HCC) remain largely unknown. In this study, we observe that P5CS is highly expressed in HCC tissues, and elevated levels of P5CS expression are associated with poor prognosis in HCC patients. Notably, the knockdown of P5CS inhibits the proliferation, migratory and invasive capabilities of HCC cells by reducing mitochondrial respiration. Furthermore, we demonstrate that SIRT2 interacts with P5CS and mediates the deacetylation of P5CS at lysines K311 and K347, thereby activating its enzymatic activity. Activated P5CS significantly enhances mitochondrial respiration, which supports the proliferation and tumorigenesis of HCC cells. In addition, SIRT2 knockdown inhibits the proliferation, migratory and invasive capabilities of HCC cells. These observations suggest that SIRT2-mediated P5CS deacetylation is a crucial signaling event through which cancer cells sustain mitochondrial respiration and promote HCC progression. This finding offers the potential for targeting SIRT2-mediated P5CS deacetylation as a therapeutic strategy for HCC.