MAT1A 激活糖酵解以促进 NSCLC 进展取决于 CCND1 的稳定。

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-10-22 DOI:10.1038/s41419-024-07113-7
Shengping Shen, Ruili Liu, Jiazheng Huang, Yingjia Sun, Qiang Tan, Qingquan Luo, Ruijun Liu
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引用次数: 0

摘要

非小细胞肺癌(NSCLC)作为全球癌症相关死亡的主要原因,仍然令人担忧。在有关蛋氨酸腺苷转移酶1A(MAT1A)在癌症中的作用和机制的争论中,我们的研究揭示了它在非小细胞肺癌中的意义。利用TCGA数据库和免疫组化染色,我们系统分析了MAT1A在NSCLC中的表达,发现了其明显的上调。为了揭示其功能和机理基础,我们在 NSCLC 细胞系中稳定敲除了 MAT1A。我们的研究结果表明,抑制 MAT1A 的表达可有效抑制 NSCLC 细胞的增殖和迁移能力,同时增强细胞凋亡。从机理上讲,我们发现抑制 MAT1A 可通过 S 期激酶相关蛋白 2(SKP2)介导的泛素化加速细胞周期关键调控因子 CCND1 的降解。值得注意的是,CCND1是MAT1A的重要伙伴,共同协调NSCLC细胞中的糖代谢。这种错综复杂的相互作用表明,MAT1A 通过保护 CCND1 蛋白的稳定性和激活糖酵解途径来促进 NSCLC 的进展,从而维持肿瘤的发生。总之,我们的研究不仅确定了 MAT1A 是 NSCLC 患者不良生存率的预后标志物,还阐明了它对癌症进展的机理贡献。这些发现为开发旨在破坏 NSCLC 中有害的 MAT1A-CCND1 糖酵解轴的靶向疗法铺平了道路。
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MAT1A activation of glycolysis to promote NSCLC progression depends on stabilizing CCND1.

Non-small cell lung cancer (NSCLC) remains a cause for concern as the leading cause of cancer-related death worldwide. Amidst ongoing debates on the role and mechanisms of methionine adenosyltransferase 1A (MAT1A) in cancer, our study sheds light on its significance in NSCLC. Leveraging TCGA database and immunohistochemical staining, we systematically analyzed MAT1A expression in NSCLC, uncovering its marked upregulation. To unravel the functional and mechanistic underpinnings, we implemented stable knockdown of MAT1A in NSCLC cell lines. Our findings converged to demonstrate that suppression of MAT1A expression effectively impeded the proliferation and migratory capabilities of NSCLC cells, while concurrently enhancing apoptosis. Mechanistically, we discovered that MAT1A depletion accelerated the degradation of CCND1, a key cell cycle regulator, through S-phase kinase-associated protein 2 (SKP2)-mediated ubiquitination. Notably, CCND1 emerged as a crucial MAT1A partner, jointly orchestrating glycolytic metabolism in NSCLC cells. This intricate interplay suggests that MAT1A promotes NSCLC progression by safeguarding CCND1 protein stability and activating glycolytic pathways, thereby sustaining tumorigenesis. In summary, our study not only identifies MAT1A as a prognostic marker for poor survival in NSCLC patients but also elucidates its mechanistic contributions to cancer progression. These findings pave the way for the development of targeted therapies aimed at disrupting the deleterious MAT1A-CCND1-glycolysis axis in NSCLC.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
期刊最新文献
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