Geng Xiaofang, Li Mengyao, Zhang Lu, Cai Yihan, Chen Xin, Mu Xiayue, Wang Jie, Liu Bowen
Xinxiang Key Laboratory of Inflammation and Immunology, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Medical Technology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
Oncogene. 2025 May 27. doi: 10.1038/s41388-025-03456-3.
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.
癌细胞通常表现出线粒体代谢增强，以满足其生长所需的能量和生物合成需求。线粒体对细胞能量需求波动的反应对于细胞适应和正常器官功能至关重要。由ALDH18A1基因编码的线粒体δ-1-吡咯啉-5-羧酸合成酶（P5CS）是脯氨酸合成的关键酶，在肿瘤发生过程中经常上调。然而，肝细胞癌（HCC）发生和发展过程中调控P5CS活性的机制仍不清楚。在本研究中，我们观察到P5CS在HCC组织中高表达，且P5CS表达水平升高与HCC患者预后不良相关。值得注意的是，敲低P5CS可通过降低线粒体呼吸来抑制HCC细胞的增殖、迁移和侵袭能力。此外，我们证明SIRT2与P5CS相互作用，并介导P5CS在赖氨酸K311和K347处的去乙酰化，从而激活其酶活性。激活的P5CS显著增强线粒体呼吸，支持HCC细胞的增殖和肿瘤发生。此外，敲低SIRT2可抑制HCC细胞的增殖、迁移和侵袭能力。这些观察结果表明，SIRT2介导的P5CS去乙酰化是癌细胞维持线粒体呼吸并促进HCC进展的关键信号事件。这一发现为靶向SIRT2介导的P5CS去乙酰化作为HCC的治疗策略提供了可能性。
