The Hippo-YAP signaling pathway promotes hepatocellular carcinoma progression by inducing FHL3 expression

The Hippo pathway plays an important role in cell proliferation, differentiation, and cancer occurrence. Yes-associated protein 1 (YAP) is a key effector molecule of Hippo pathway. Previous studies have found abnormal YAP overexpression in many solid tumors, including hepatocellular carcinoma (HCC). Here, we attempt to explore the cancer-promoting mechanism of YAP in HCC. The target gene of Hippo-YAP pathway, Four and a half LIM domain protein 3 (FHL3), was screened by spontaneous hydrodynamic tumor model with YAP participation and two publicly HCC microarray sets. Western blot (WB) and immunohistochemical (IHC) showed high protein levels of FHL3 in tumor tissues and the expression of FHL3 was associated with poorer prognosis. The biological effect experiments showed that FHL3 significantly promoted the progression of HCC. FHL3 interacted with MYC-associated zinc finger protein (MAZ) to recruit MAZ binding to the G-quadruplexes (G4s) structure, which promoted Kirsten rat sarcoma viral oncogene homologue (KRAS) transcription and activation of its downstream signal. Down-regulating KRAS expression inhibited the promoting effect of YAP-FHL3 signaling on HCC. In addition, transactivation of FHL3 mediated by YAP was verified by luciferase reporter assay and chromatin immunoprecipitation (ChIP). FHL3 knockdown inhibited the tumor-promoting effect of YAP and significantly delayed the tumorigenesis and progression caused by YAP. Finally, clinical data validated the correlation between YAP, FHL3, and KRAS expression. In conclusion, we identified a new target of Hippo-YAP signaling, FHL3, which interacts with MAZ to promote KRAS transcription and downstream oncogenic signaling pathway activation, thereby promoting HCC progression.