ISGylation of EMD promotes its interaction with PDHA to inhibit aerobic oxidation in lung adenocarcinoma.
ISGylation of EMD promotes its interaction with PDHA to inhibit aerobic oxidation in lung adenocarcinoma.
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EMD 的 ISG 化促进其与 PDHA 的相互作用，抑制肺腺癌的有氧氧化
DOI：
10.1111/jcmm.17536
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发表时间：
2022-10
影响因子：
5.3
通讯作者：
中科院分区：
文献类型：
--
作者：
由骨架蛋白的失调引起的异常核结构是肿瘤细胞中的常见现象。然而，骨骼蛋白如何促进肿瘤发生仍然没有被发现。本研究揭示了骨骼蛋白Emerin（EMD）促进糖代谢诱导肺腺癌（LUAD）的机制。首先，我们发现EMD在LUAD中高表达，并促进LUAD的恶性表型。EMD的高表达可能与其低水平的泛素化有关。此外，EMD的赖氨酸37处的ISG化抑制赖氨酸36泛素化并上调EMD稳定性。我们进一步探讨了EMD可以抑制有氧氧化和促进糖酵解。从机制上讲，EMD通过其β-catenin相互作用结构域与PDHA结合，刺激丝氨酸293和300磷酸化并抑制PDHA表达，促进应进入有氧氧化途径的葡萄糖的糖酵解，并且EMD ISG化对于EMD-PDHA相互作用至关重要。在临床LUAD标本中，EMD与PDHA呈负相关，而与EMD ISGylation、肿瘤分期和直径呈正相关。在高血糖水平的LUAD中，EMD表达和ISG化水平较高。总之，EMD通过与PDHA相互作用抑制好氧氧化而促进LUAD的发生。限制EMD的促癌作用可能有助于LUAD治疗。
Abnormal nuclear structure caused by dysregulation of skeletal proteins is a common phenomenon in tumour cells. However, how skeletal proteins promote tumorigenesis remains uncovered. Here, we revealed the mechanism by which skeletal protein Emerin (EMD) promoted glucose metabolism to induce lung adenocarcinoma (LUAD). Firstly, we identified that EMD was highly expressed and promoted the malignant phenotypes in LUAD. The high expression of EMD might be due to its low level of ubiquitination. Additionally, the ISGylation at lysine 37 of EMD inhibited lysine 36 ubiquitination and upregulated EMD stability. We further explored that EMD could inhibit aerobic oxidation and stimulate glycolysis. Mechanistically, via its β‐catenin interaction domain, EMD bound with PDHA, stimulated serine 293 and 300 phosphorylation and inhibited PDHA expression, facilitated glycolysis of glucose that should enter the aerobic oxidation pathway, and EMD ISGylation was essential for EMD‐PDHA interaction. In clinical LUAD specimens, EMD was negatively associated with PDHA, while positively associated with EMD ISGylation, tumour stage and diameter. In LUAD with higher glucose level, EMD expression and ISGylation were higher. Collectively, EMD was a stimulator for LUAD by inhibiting aerobic oxidation via interacting with PDHA. Restricting cancer‐promoting role of EMD might be helpful for LUAD treatment.
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影响因子：
--
作者：
Liu F;Zhang W;You X;Liu Y;Li Y;Wang Z;Wang Y;Zhang X;Ye L
通讯作者：
Ye L
影响因子：
3.6
作者：
Hoang Van Tong;Nghiem Xuan Hoan;Nguyen Linh Toan
通讯作者：
Nguyen Linh Toan
影响因子：
21.3
作者：
Kirby TJ;Lammerding J
通讯作者：
Lammerding J
DOI：
10.1158/1541-7786.mcr-20-0413
发表时间：
2021-07
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Liddane AG;McNamara CA;Campbell MC;Mercier I;Holaska JM
通讯作者：
Holaska JM
影响因子：
5.6
作者：
Liddane AG;Holaska JM
通讯作者：
Holaska JM