SIRT7 stabilizes β-catenin and promotes canonical Wnt activation via upregulating FZD7.

AIMS: The dysregulated Wnt/β-Catenin signaling pathway leads to occurrence of various diseases, and abnormal activation of β-Catenin is a major characteristic of human HCC. FZD7 is a positive regulator of the Wnt/β-catenin signaling pathway, and its upregulation is related to increase of β-catenin expression and carcinogenesis in human HCC. However, mechanisms underlying FZD7 upregulation in HCC remain elusive.

MAIN METHODS: Nuclear cytosol fractionation, immunofluorescence and Top-Flash were used to detect the activation of β-Catenin. Protein half-life and ubiquitination assays were applied to evaluate protein stability. RNA-seq combined with qRT-PCR was used to evaluate differential gene expressions after SIRT7 knockdown. Wound healing and transwell assays were used to measure cancer cell migration.

KEY FINDINGS: SIRT7-mediated FZD7 expression is essential for stability and activation of β-catenin. Knockdown SIRT7 in HCC cells resulted in enhanced binding of β-catenin to the DC, decreased its stability, nuclear localization and activation. Knockdown FZD7 reversed SIRT7 overexpression mediated β-catenin stabilization and impairment of binding of β-catenin to the DC. At molecular level, SIRT7 promotes FZD7 expression via upregulating transcription factor PU.1, knockdown PU.1 abolished SIRT7-mediated upregulation of FZD7. Finally, we confirmed that FZD7 was responsible for SIRT7-mediated β-catenin stabilization and HCC cells migration. By using clinical samples, we observed strong positive correlations between SIRT7 and PU.1, FZD7, p-GSK3β and β-Catenin in human HCC.

SIGNIFICANCE: Our results thus revealed a previously undisclosed role of SIRT7 in regulating the canonical Wnt/β-catenin signaling pathway, thereby offering additional evidence that SIRT7 holds promise as a novel therapeutic target for human HCC.