Cancer Research Center, School of Medicine, Xiamen University, Xiamen 361102, China.
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
Cell Rep. 2024 Aug 27;43(8):114604. doi: 10.1016/j.celrep.2024.114604. Epub 2024 Aug 14.
Exo70, a key exocyst complex component, is crucial for cell motility and extracellular matrix (ECM) remodeling in cancer metastasis. Despite its potential as a drug target, Exo70's post-translational modifications (PTMs) are poorly characterized. Here, we report that Exo70 is transamidated on Gln5 with Lys56 of cystatin A by transglutaminases TGM1 and TGM3, promoting tumor metastasis. This modification enhances Exo70's association with other exocyst subunits, essential for secreting matrix metalloproteinases, forming invadopodia, and delivering integrins to the leading edge. Tumor suppressor liver kinase B1 (LKB1), whose inactivation accelerates metastasis, phosphorylates TGM1 and TGM3 at Thr386 and Thr282, respectively, to inhibit their interaction with Exo70 and the following transamidation. Cantharidin, a US Food and Drug Administration (FDA)-approved drug, inhibits Exo70 transamidation to restrain tumor cell migration and invasion. Together, our findings highlight Exo70 transamidation as a key molecular mechanism and target and propose cantharidin as a therapeutic strategy with direct clinical translational value for metastatic cancers, especially those with LKB1 loss.
外泌体复合物的关键组成部分 Exo70 对于癌症转移中的细胞迁移和细胞外基质（ECM）重塑至关重要。尽管它具有作为药物靶点的潜力，但 Exo70 的翻译后修饰（PTMs）的特征还很差。在这里，我们报告说 Exo70 通过转谷氨酰胺酶 TGM1 和 TGM3 在 Gln5 上被赖氨酸 56 酰胺化修饰，从而促进肿瘤转移。这种修饰增强了 Exo70 与其他外泌体亚基的结合，这对于分泌基质金属蛋白酶、形成侵袭伪足以及将整合素递送至前缘是必不可少的。肿瘤抑制因子肝激酶 B1（LKB1）的失活加速了转移，它分别在 Thr386 和 Thr282 处磷酸化 TGM1 和 TGM3，以抑制它们与 Exo70 的相互作用和随后的酰胺化。斑蝥素是一种获得美国食品和药物管理局（FDA）批准的药物，可抑制 Exo70 的酰胺化，从而抑制肿瘤细胞的迁移和侵袭。总之，我们的研究结果强调了 Exo70 酰胺化作为一个关键的分子机制和靶点，并提出斑蝥素作为一种具有直接临床转化价值的治疗策略，适用于转移性癌症，特别是那些 LKB1 缺失的癌症。
