Department of Pathology, Third Xiangya Hospital of Central South University, Changsha, China.
921 Hospital of the Chinese People's Liberation Army Joint Logistic Support Force, Changsha, China.
Biochim Biophys Acta Gen Subj. 2024 Oct;1868(10):130683. doi: 10.1016/j.bbagen.2024.130683. Epub 2024 Jul 31.
Pancreatic cancer (PC) is characterized by a poor prognosis and limited treatment options. Ferroptosis plays an important role in cancer, SET and MYND domain-containing protein 2 (SMYD2) is widely expressed in various cancers. However, the role of SMYD2 in regulating ferroptosis in PC remains unexplored. This study aimed to investigate the role of SMYD2 in mediating ferroptosis and its mechanistic implications in PC progression.
The levels of SMYD2, c-Myc, and NCOA4 were assessed in PC tissues, and peritumoral tissues. SMYD2 expression was further analyzed in human PC cell lines. In BxPC3 cells, the expression of c-Myc, NCOA4, autophagy-related proteins, and mitochondrial morphology, was evaluated following transfection with si-SMYD2 and treatment with autophagy inhibitors and ferroptosis inhibitors. Ferroptosis levels were quantified using flow cytometry and ELISA assays. RNA immunoprecipitation was conducted to elucidate the interaction between c-Myc and NCOA4 mRNA. A xenograft mouse model was constructed to validate the impact of SMYD2 knockdown on PC growth.
SMYD2 and c-Myc were found to be highly expressed in PC tissues, while NCOA4 showed reduced expression. Among the PC cell lines studied, BxPC3 cells exhibited the highest SMYD2 expression. SMYD2 knockdown led to decreased c-Myc levels, increased NCOA4 expression, reduced autophagy-related protein expression, mitochondrial shrinkage, and heightened ferroptosis levels. Additionally, an interaction between c-Myc and NCOA4 was identified. In vivo, SMYD2 knockdown inhibited tumor growth.
Targeting SMYD2 inhibits PC progression by promoting ferritinophagy-dependent ferroptosis through the c-Myc/NCOA4 axis. These findings provide insights into potential diagnostic and therapeutic strategies for PC.
胰腺癌（PC）的预后较差，治疗选择有限。铁死亡在癌症中发挥重要作用，SET 和 MYND 结构域包含蛋白 2（SMYD2）广泛表达于各种癌症中。然而，SMYD2 在调节 PC 中的铁死亡作用仍未被探索。本研究旨在研究 SMYD2 在介导铁死亡及其在 PC 进展中的机制意义中的作用。
评估 PC 组织和肿瘤旁组织中 SMYD2、c-Myc 和 NCOA4 的水平。进一步分析人 PC 细胞系中 SMYD2 的表达。在 BxPC3 细胞中，转染 si-SMYD2 并使用自噬抑制剂和铁死亡抑制剂处理后，评估 c-Myc、NCOA4、自噬相关蛋白和线粒体形态的表达。使用流式细胞术和 ELISA 测定法定量铁死亡水平。进行 RNA 免疫沉淀以阐明 c-Myc 和 NCOA4 mRNA 之间的相互作用。构建异种移植小鼠模型以验证 SMYD2 敲低对 PC 生长的影响。
SMYD2 和 c-Myc 在 PC 组织中表达较高，而 NCOA4 表达降低。在所研究的 PC 细胞系中，BxPC3 细胞中 SMYD2 表达最高。SMYD2 敲低导致 c-Myc 水平降低、NCOA4 表达增加、自噬相关蛋白表达减少、线粒体收缩和铁死亡水平升高。此外，鉴定到 c-Myc 和 NCOA4 之间的相互作用。在体内，SMYD2 敲低抑制肿瘤生长。
靶向 SMYD2 通过 c-Myc/NCOA4 轴促进铁蛋白自噬依赖性铁死亡抑制 PC 进展。这些发现为 PC 的潜在诊断和治疗策略提供了思路。
