Fat1 suppresses the tumor‐initiating ability of nonsmall cell lung cancer cells by promoting Yes‐associated protein 1 nuclear‐cytoplasmic translocation.

The suppressive roles of Fat1 have been widely revealed in various tumors. However, its effects on the tumor‐initiating ability of nonsmall cell lung cancer (NSCLC) cells have never been elucidated. Currently, we identified that a higher level of Fat1 mRNA expression predicted a longer overall survival and first‐progression survival of lung cancer patients, especially in adenocarcinoma patients. In addition, Fat1 mRNA exhibited a lower level in lung cancer tissues relative to that in normal tissues. Functionally, we focused on the effects of Fat1 on the tumor‐initiating ability of NSCLC cells and we found that Fat1 overexpression decreased the expression of tumor‐initiating markers. Furthermore, overexpression of Fat1 reduced ALDH1 activity and sphere‐formation ability of NSCLC cells. Mechanistically, we revealed that Fat1 promoted the nuclear‐cytoplasmic transportation of YAP1 (Yes‐associated protein 1), a critical executor of Hippo signaling, and a mutant form of YAP (YAP‐5SA), which can escape from LATS1/2‐mediated phosphorylation, rescued the Fat1‐mediated inhibition on the tumor‐initiating ability of NSCLC cells. This work prompts that Fat1 suppresses the tumor‐initiating ability of NSCLC cells by activating Hippo signaling. [ABSTRACT FROM AUTHOR]