Upregulation of TWNK promotes proliferation and invasion of liver cancer by enhancing mitochondrial respiration.

TWNK, a mitochondrial hexameric DNA helicase, is crucial for the replication of mtDNA. Nonetheless, its biological functions in human cancers still largely unexplored. In this study, we reveal that TWNK expression is significantly elevated in hepatocellular carcinoma (HCC) tissues, and its elevation associates with poor patient prognosis. We further demonstrate that TWNK knockdown suppresses HCC proliferation and metastasis by inducing G1-to-S cell cycle arrest and inhibiting epithelial-to-mesenchymal transition (EMT). Conversely, forced TWNK expression enhances HCC cell proliferation and motility. Mechanistically, TWNK promotes HCC cell proliferation and invasion through augmenting mitochondrial DNA (mtDNA) content, which in turn boosts mitochondrial respiration and energy production through upregulation of mtDNA-encoded electron transport chain (ETC) genes. Additionally, we found that DNA hypomethylation and decreased miR-766-3p expression contribute, at least in part, to the upregulation of TWNK in HCC cells. Together, our results elucidate a novel oncogenic role for TWNK in HCC and highlight its potential as a target for therapeutic intervention.