Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing 100050, China.
Int J Mol Sci. 2023 Apr 12;24(8):7150. doi: 10.3390/ijms24087150.
The metabolic enzymes involved in one-carbon metabolism are closely associated with tumor progression and could be potential targets for cancer therapy. Recent studies showed that serine hydroxymethyltransferase 2 (SHMT2), a crucial enzyme in the one-carbon metabolic pathway, plays a key role in tumor proliferation and development. However, the precise role and function of SHMT2 in gastric cancer (GC) remain poorly understood. In this study, we presented evidence that SHMT2 was necessary for hypoxia-inducible factor-1α (HIF1α) stability and contributed to GC cells' hypoxic adaptation. The analysis of datasets retrieved from The Cancer Genome Atlas and the experimentation with human cell lines revealed a marked increase in SHMT2 expression in GC. The SHMT2 knockdown in MGC803, SGC7901, and HGC27 cell lines inhibited cell proliferation, colony formation, invasion, and migration. Notably, SHMT2 depletion disrupted redox homeostasis and caused glycolytic function loss in GC cells under hypoxic circumstances. Mechanistically, we discovered SHMT2 modulated HIF1α stability, which acted as a master regulator of hypoxia-inducible genes under hypoxic conditions. This, in turn, regulated the downstream VEGF and STAT3 pathways. The in vivo xenograft experiments showed that SHMT2 knockdown markedly reduced GC growth. Our results elucidate the novel function of SHMT2 in stabilizing HIF1α under hypoxic conditions, thus providing a potential therapeutic strategy for GC treatment.
一碳代谢中涉及的代谢酶与肿瘤的进展密切相关，可能成为癌症治疗的潜在靶点。最近的研究表明，丝氨酸羟甲基转移酶 2（SHMT2）作为一碳代谢途径中的关键酶，在肿瘤的增殖和发展中起着关键作用。然而，SHMT2 在胃癌（GC）中的确切作用和功能仍知之甚少。在这项研究中，我们提供了证据表明 SHMT2 对于缺氧诱导因子-1α（HIF1α）的稳定性是必需的，并有助于 GC 细胞的缺氧适应。从癌症基因组图谱（The Cancer Genome Atlas）中检索的数据集的分析和人类细胞系的实验表明，GC 中 SHMT2 的表达明显增加。在 MGC803、SGC7901 和 HGC27 细胞系中敲低 SHMT2 抑制了细胞增殖、集落形成、侵袭和迁移。值得注意的是，SHMT2 的耗竭破坏了 GC 细胞在缺氧条件下的氧化还原平衡，并导致糖酵解功能丧失。在机制上，我们发现 SHMT2 调节 HIF1α 的稳定性，HIF1α 作为缺氧诱导基因在缺氧条件下的主调控因子。这反过来又调节下游的 VEGF 和 STAT3 途径。体内异种移植实验表明，SHMT2 敲低显著降低了 GC 的生长。我们的研究结果阐明了 SHMT2 在缺氧条件下稳定 HIF1α 的新功能，为 GC 的治疗提供了一种潜在的治疗策略。
