ROS-induced cytosolic release of PGAM5 accelerates cancer progression via MST3-YAP axis

Aberrant mtROS release in response to mitochondrial stress are considered to be a major novel feature of neoplastic transformation. However, the molecular mechanisms by which mtROS contribute to CRC development have not been fully elucidated. In this study, we showed that upon sensing the mtROS signal, the mitochondrially localized phosphatase PGAM5 undergoes cleavage in the mitochondrial transmembrane domain, and then the Cleaved PGAM5 is released into the cytoplasm. Subsequently, Cleaved PGAM5 binds to the kinase MST3 in the cytoplasm to promote MST3 dephosphorylation, resulting in a decrease in MST3 activity. Importantly, MST3 inactivation failed to regulate YAP phosphorylation, leading to YAP translocation into the nucleus, consequently promoting CRC proliferation and metastasis. Collectively, our findings identified the PGAM5-MST3-YAP axis as an important molecular mechanism through which mtROS promotes CRC development. Overall design: To investigate the function of MST3 in CRC regulation, we generated MST3 intestinal epithelial knockout mice and treated them with AOM&DSS.We then performed gene expression profiling using mRNA-seq data from the intestinal epithelium of littermate mice.

线粒体活性氧（mtROS）在响应线粒体应激时的异常释放，被认为是肿瘤转化的一项重要新特征。然而，mtROS促进结直肠癌（CRC）发生发展的分子机制尚未完全阐明。本研究发现，在感知mtROS信号后，定位于线粒体的磷酸酶PGAM5会在线粒体跨膜结构域处发生切割，随后切割型PGAM5被释放至细胞质中。后续，切割型PGAM5会与细胞质内的激酶MST3结合，促进MST3发生去磷酸化，进而导致MST3活性下降。值得注意的是，MST3失活无法调控YAP的磷酸化，进而促使YAP转位入核，最终促进结直肠癌的增殖与转移。综上，本研究的发现明确了PGAM5-MST3-YAP信号轴是mtROS促进结直肠癌发生发展的重要分子机制。
总体实验设计：为探究MST3在结直肠癌调控中的功能，我们构建了MST3肠道上皮特异性敲除小鼠，并使用AOM&DSS（偶氮甲烷-葡聚糖硫酸钠）对其进行处理。随后，我们利用同窝小鼠肠道上皮组织的mRNA测序（mRNA-seq）数据开展了基因表达谱分析。