PUM1 Promotes Tumor Progression by Activating DEPTOR-Meditated Glycolysis in Gastric Cancer.
PUM1 Promotes Tumor Progression by Activating DEPTOR-Meditated Glycolysis in Gastric Cancer.
复制标题
DOI：
10.1002/advs.202301190
复制
发表时间：
2023-09
期刊：
影响因子：
15.1
通讯作者：
Zhang, Changhua
中科院分区：
文献类型：
--
作者：
Yin, Songcheng;Liu, Huifang;Zhou, Zhijun;Xu, Xiaoyu;Wang, Pengliang;Chen, Wei;Deng, Guofei;Wang, Han;Yu, Hong;Gu, Liang;Huo, Mingyu;Li, Min;Zeng, Leli;He, Yulong;Zhang, Changhua
RNA结合蛋白(RBPs)在肿瘤的发生和发展中起重要作用，但其在胃癌(GC)中的功能仍很难捉摸。据报道，PUM1是一种RBP，通过对GC中含有DEP结构域的哺乳动物雷帕霉素靶标(MTOR)相互作用蛋白(DEPTOR)的转录后调节而诱导代谢重编程。在临床标本中，PUM1的高表达与复发、转移和低存活率有关。体内外实验表明，PUM1基因的敲除可抑制胃癌细胞的增殖和转移。此外，RNA测序和生物信息学分析表明，PUM1具有丰富的糖酵解基因特征。代谢组学研究证实，PUM1缺乏会抑制糖酵解代谢。在机制上，PUM1直接与DEPTOR基因的Pumilio反应元件结合，维持转录的稳定性，并通过转录后途径阻止DEPTOR的降解。PUM1介导的DEPTOR上调抑制mTORC1，并缓解正常情况下mTORC1向PI3K传递的抑制反馈信号，从而激活PI3K-Akt信号并持续糖酵解。总之，这些结果揭示了PUM1在调控DEPTOR依赖的GC进展中的关键表观遗传学作用。这些结论支持PUM1抑制剂作为GC代谢靶向治疗策略的进一步临床研究。PUM1是一种RNA结合蛋白，通过转录后调控含DEP结构域的哺乳动物TOR(MTOR)相互作用蛋白(DEPTOR)在胃癌中诱导代谢重编程。本研究揭示了PUM1在调节依赖DEPTOR的GC糖酵解代谢中的关键表观遗传学作用，支持了PUM1抑制剂作为GC代谢靶向策略的进一步临床研究。
RNA‐binding proteins (RBPs) play essential roles in tumorigenesis and progression, but their functions in gastric cancer (GC) remain largely elusive. Here, it is reported that Pumilio 1 (PUM1), an RBP, induces metabolic reprogramming through post‐transcriptional regulation of DEP domain‐containing mammalian target of rapamycin (mTOR)‐interacting protein (DEPTOR) in GC. In clinical samples, elevated expression of PUM1 is associated with recurrence, metastasis, and poor survival. In vitro and in vivo experiments demonstrate that knockdown of PUM1 inhibits the proliferation and metastasis of GC cells. In addition, RNA‐sequencing and bioinformatics analyses show that PUM1 is enriched in the glycolysis gene signature. Metabolomics studies confirm that PUM1 deficiency suppresses glycolytic metabolism. Mechanistically, PUM1 binds directly to DEPTOR mRNA pumilio response element to maintain the stability of the transcript and prevent DEPTOR degradation through post‐transcriptional pathway. PUM1‐mediated DEPTOR upregulation inhibits mTORC1 and alleviates the inhibitory feedback signal transmitted from mTORC1 to PI3K under normal conditions, thus activating the PI3K–Akt signal and glycolysis continuously. Collectively, these results reveal the critical epigenetic role of PUM1 in modulating DEPTOR‐dependent GC progression. These conclusions support further clinical investigation of PUM1 inhibitors as a metabolic‐targeting treatment strategy for GC. Pumilio 1 (PUM1), an RNA binding protein, induces metabolic reprogramming through post‐transcriptional regulation of DEP domain‐containing mammalian TOR (mTOR)‐interacting protein (DEPTOR) in gastric cancer (GC). This study reveals the critical epigenetic role of PUM1 in modulating DEPTOR‐dependent GC glycolytic metabolism, supporting further clinical investigation of PUM1 inhibitors as a metabolic‐targeting strategy for GC.
登录
查看更多内容
影响因子：
82.9
作者：
Gao, Hui;Korn, Joshua M.;Sellers, William R.
通讯作者：
Sellers, William R.
影响因子：
4.8
作者：
Parvani, Jenny G.;Davuluri, Gangarao;Wendt, Michael K.;Espinosa, Christine;Tian, Maozhen;Danielpour, David;Sossey-Alaoui, Khalid;Schiemann, William P.
通讯作者：
Schiemann, William P.
影响因子：
3.9
作者：
Edwards, Thomas A.
通讯作者：
Edwards, Thomas A.
影响因子：
8
作者：
Buzzai, M;Bauer, DE;Thompson, CB
通讯作者：
Thompson, CB
全基因组 CRISPR-Cas9 筛选鉴定出 NF-kappa B/E2F6 负责胶质母细胞瘤中与 EGFRvIII 相关的替莫唑胺耐药性
影响因子：
15.1
作者：
Huang, Kai;Liu, Xing;Kang, Chunsheng
通讯作者：
Kang, Chunsheng