SDHB deficiency promotes TGFβ-mediated invasion and metastasis of colorectal cancer through transcriptional repression complex SNAIL1-SMAD3/4

Succinate dehydrogenase (SDH) is a heterotetrameric complex, among which the catalytic core SDHB loss-of-function mutations lead to mitochondrial enzyme SDH dysfunction and are associated with cancer formation. However, the impact of SDHB loss on colorectal carcinoma and the underlying mechanisms are largely unknown. In this study, we found a coherent decreased SDHB expression both in human colorectal cancer (CRC) samples and CRC cell lines. Combined clinical analysis in a cohort of 43 CRC patients demonstrated a correlation between reduced SDHB activity and a more advanced clinical phenotype regarding lymphatic and distant metastasis. Applying genetic interference and cellular function approaches, we found that knocking down SDHB promoted cell migration and invasion through enabling epithelial-mesenchymal transition (EMT), and inverse results of SDHB overexpression further confirmed our theory. Mechanical exploration revealed that SDHB knockdown could activate TGF beta signaling pathway, more precisely through up-regulation of a tight-junction transcriptional repression complex SNAIL1-SMAD3/SMAD4, thus contributed to the increase in metastasis. In conclusion by identifying SNAIL1-SMAD3/SMAD4 as essential for the TGF beta-mediated tumorigenic capacity in SDHB-deficient CRC cells, this study revealed a critical mechanical vulnerability for potential future therapeutic target of SDHB-associated CRC.