Mst1 regulates colorectal cancer stress response via inhibiting Bnip3-related mitophagy by activation of JNK/p53 pathway.

The Hippo-Mst1 pathway is associated with tumor development and progression. However, little evidence is available for its role in colorectal cancer (CRC) stress response via mitochondrial homeostasis. In this study, we conducted gain-of function assay about Mst1 in CRC via adenovirus transfection. Then, cellular viability and apoptosis were measured via MTT, TUNEL assay, and typan blue staining. Mitochondrial function was detected via JC1 staining, mPTP opening assay, and immunofluorescence of cyt-c. Mitophagy was observed via western blots and immunofluorescence. Cell migration and proliferation were evaluated via Transwell and BrdU assay. Western blots were used to analyze the signaling pathways with JNK inhibitors or p53 siRNA. We found that Mst1 was down-regulated in CRC. Overexpression of Mst1 induced CRC apoptosis and impaired cell proliferation and migration. Functional studies have illustrated that recovery of Mst1 could activate JNK pathway which upregulated the p53 expression. The latter repressed Bnip3 transcription and activity, leading to the mitophagy arrest. The defective mitophagy impaired mitochondrial homeostasis, evoked cellular oxidative stress, and initiated the mitochondrial apoptosis. Meanwhile, bad-structured mitophagy also hindered the cancer proliferation via CyclinD/E. Moreover, Mst1-suppressed mitophagy was associated with CRC migration inhibition via regulation of CXCR4/7 expression. Collectively, our data described the comprehensive role of Mst1 in colorectal cancer stress response involving apoptosis, mobilization, and growth via handling mitophagy by JNK/p53/Bnip3 pathways.