C-Myc-activated FKBP4 promotes hepatocellular carcinoma cell proliferation and invasion by regulating the PHLPP1/AKT pathway

Although FKBP prolyl isomerase 4 (FKBP4) is upregulated in WHV/c-Myc mouse livers and hepatocellular carcinoma (HCC) tissues, its clinical significance, role in tumor progression, and the underlying mechanism of involvement in HCC remain unclear. In this study, data from public databases and our HCC cohort showed upregulated FKBP4 expression in tumor tissues. Increased FKBP4 levels was associated with malignant clinical features of HCC, including tumor diameter ≥ 3 cm, poor differentiation, and advanced tumor stage. COX regression analysis recognized FKBP4 as one of the independent risk factors for poor overall survival of patients with HCC. The proliferation, migration, and invasion of SNU449 and Huh7 cells were significantly reduced by FKBP4 knockdown, but enhanced by FKBP4 overexpression. c-Myc positively regulated FKBP4 expression in HCC cells. Mechanistically, c-Myc directly binds to the FKBP4 promoter and activates gene transcription. The interaction of FKBP4 with PH domain and leucine rich repeat protein Phosphatase 1 (PHLPP1) enhanced its ubiquitination and degradation, subsequently activating the protein kinase B (Akt) pathway. Akt inhibition (with MK-2206) and PHLPP1 overexpression prominently attenuated the FKBP4-induced increase in HCC cell proliferation and invasion. FKBP4 knockdown suppressed the growth of SNU449 cells in vivo. PHLPP1 overexpression markedly abolished FKBP4-enhanced HCC growth in mice. In conclusion, FKBP4 overexpression was correlated with poor prognosis in patients with HCC. c-Myc transcriptionally activated-FKBP4 interacted with PHLPP1 to enhance its ubiquitin-mediated degradation, thereby enhancing the Akt pathway and facilitating HCC cell proliferation and invasion. Our findings provide a theoretical basis for targeting FKBP4 in treating HCC.

C-Myc; FKBP4; Hepatocellular carcinoma; PHLPP1; Tumor progression.