KLHL23 Regulates a Novel Positive-Feedback Signaling Loop of EMT Maintaining the Mesenchymal State of Cancer Cells during Metastasis

Epithelial-mesenchymal transition (EMT) is initiated and regulated by a transcriptional reprogramming in response to microenvironmental cues. How cancer cells overcome the lack of such cues during the metastatic journey remains unclear. Here we report a novel positive-feedback loop of EMT that maintains the mesenchymal traits of cancer cells during metastasis. Using subgenome-wide screening, we identified KLHL23 as a tumor invasion suppressor, which binds to actin and suppresses actin-filament formation. Silencing or ectopic expression of KLHL23 induces EMT or MET (mesenchymal-epithelial transition), respectively, through its action on actin dynamics. Increased actin-dynamics by silencing KLHL23 or treatment with F-actin disruptors or inducers enhances the EMT transcriptional reprogramming via the induction of ROS, HIF-1a, HIF-2a and NOTCH signalling pathways in cancer cells under stress or ongoing EMT. Downregulation of KLHL23 is found in human liver and pancreatic cancers and associated with tumor metastasis and poor prognosis.

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