Wang Zexuan, Guo Yaoyu, Hu Kefei, He Tingjiang, Qin Tong, Zhang Ludan, Xu Fang, Xu Yuanzhi, Cheng Mingjiao, Zhang Jintao, Zhao Qianwei
Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China.
BGI College, Zhengzhou University, Zhengzhou, China.
NPJ Precis Oncol. 2025 May 16;9(1):143. doi: 10.1038/s41698-025-00930-9.
Phosphoglycerate mutase 2 (PGAM2) is a crucial glycolytic enzyme. Recently, we have found that both the protein and acetylation levels of PGAM2 are down-regulated in hepatocellular carcinoma (HCC) tissues. However, the functional significance of PGAM2 in HCC progression remains poorly characterized. In this study, we demonstrated that PGAM2 functioned as a tumor suppressor in HCC progression, and knockdown of PGAM2 promoted proliferation of HCC cells and tumor growth both in vitro and in vivo. Moreover, we identified lysine 100 (K100) in PGAM2 as the predominant deacetylation site of sirtuin-2 (SIRT2), and that deacetylation of K100 destabilized PGAM2 by promoting its ubiquitination and degradation. Importantly, we discovered that PGAM2 suppressed aerobic glycolysis through an enzymatic activity-independent mechanism in HCC cells. Mechanistic investigations revealed that PGAM2 knockdown upregulated lactate dehydrogenase A (LDHA) expression via activation of the signal transducer and activator of transcription 3 (STAT3). Furthermore, we found that knockdown of PGAM2 sensitized HCC cells to sorafenib treatment. In conclusion, these findings elucidate the tumor-suppressive role of PGAM2 in HCC progression and its post-translational regulation through SIRT2-mediated deacetylation, which provide novel biomarkers and therapeutic targets for HCC treatment.
磷酸甘油酸变位酶2（PGAM2）是一种关键的糖酵解酶。最近，我们发现PGAM2的蛋白水平和乙酰化水平在肝细胞癌（HCC）组织中均下调。然而，PGAM2在HCC进展中的功能意义仍未得到充分表征。在本研究中，我们证明PGAM2在HCC进展中起肿瘤抑制作用，敲低PGAM2可促进HCC细胞增殖以及体内外肿瘤生长。此外，我们确定PGAM2中的赖氨酸100（K100）是沉默调节蛋白2（SIRT2）的主要去乙酰化位点，K100的去乙酰化通过促进其泛素化和降解使PGAM2不稳定。重要的是，我们发现PGAM2通过一种不依赖酶活性的机制抑制HCC细胞中的有氧糖酵解。机制研究表明，敲低PGAM2通过激活信号转导和转录激活因子3（STAT3）上调乳酸脱氢酶A（LDHA）的表达。此外，我们发现敲低PGAM2使HCC细胞对索拉非尼治疗敏感。总之，这些发现阐明了PGAM2在HCC进展中的肿瘤抑制作用及其通过SIRT2介导的去乙酰化进行的翻译后调控，这为HCC治疗提供了新的生物标志物和治疗靶点。
