Decreased Expression of FAT4 Promotes Multiple Myeloma Proliferation and Migration by Targeting the Hippo/YAP Pathway.

FAT4 is a member of the protocadherin family and plays an important role in various types of tumors. Multiple myeloma (MM) is a common hematological malignancy. Whole-exome sequencing revealed that FAT4 is a frequently mutated driver gene of MM, but its biological function in MM remains elusive. We performed targeted gene sequencing on MM cells isolated from 161 patients and retrospectively analyzed the clinical data of these patients. The mutation frequency of FAT4 in newly diagnosed MM patients was 15.5%, ranking as the sixth most frequently mutated gene. FAT4 mutations were associated with poor prognosis of MM and decreased expression of FAT4. In vitro experiments demonstrated that FAT4 knockdown promoted the proliferation and migration in MM cells. We then confirmed these findings in vivo using zebrafish and mouse models. We further revealed that FAT4 exerted tumor suppressor effects by targeting the Hippo/YAP pathway in MM. Knockdown of FAT4 promoted the nuclear translocation of YAP. Interestingly, FAT4 did not regulate YAP nuclear entry through the canonical phosphorylation cascade. Instead, coimmunoprecipitation assays revealed the interaction between FAT4 and YAP. This interaction retained YAP in the cytoplasm, thereby blocking its nuclear translocation. Our findings highlight the tumor-suppressive role of FAT4 in MM and uncover a novel mechanism by which FAT4 regulates the Hippo/YAP pathway.