FoxM1 Promotes β-Catenin Nuclear Localization and Controls Wnt Target-Gene Expression and Glioma Tumorigenesis

Abstract

SUMMARY Wnt/β-catenin signaling is essential for stem cell regulation and tumorigenesis, but its molecular mechanisms are not fully understood. Here, we report that FoxM1 is a downstream component of Wnt signaling and is critical for β-catenin transcriptional function in tumor cells. Wnt3a increases the level and nuclear translocation of FoxM1, which binds directly to β-catenin and enhances β-catenin nuclear localization and transcriptional activity. Genetic deletion of FoxM1 in immortalized neural stem cells abolishes β-catenin nuclear localization. FoxM1 mutations that disrupt the FoxM1–β-catenin interaction or FoxM1 nuclear import prevent β-catenin nuclear accumulation in tumor cells. FoxM1–β-catenin interaction controls Wnt target gene expression and is required for glioma formation, and represents a mechanism for canonical Wnt signaling during tumorigenesis.

Nuclear phosphorylated Y142 β-catenin accumulates in astrocytomas and glioblastomas and regulates cell invasion

“…20 Furthermore, Wnt/b-catenin signaling is regulated by PLAGL2 and FoxM1 proto-oncogenes during gliomagenesis. 18,22 Here, we identified PY142 b-catenin as a nuclear b-catenin form that signals through transcriptional regulation in GBM. PY142 b-catenin is different from classical active b-catenin: PY142 b-catenin accumulates in the nucleus already in astrocytoma (grade II and III) samples and correlates with high levels of the migration marker Snail/Slug in tumor biopsies.…”

“…[19][20][21] Overexpression of the Forkhead box M1 (FoxM1) transcription factor represents a critical mechanism further contributing to b-catenin signaling in GBM. 22 FoxM1 promotes b-catenin nuclear accumulation and together they form a complex with TCF4 required for glioma stem cell self-renewal and gliomagenesis. 22,23 Crosstalk between EGFR, c-Met and Wnt/b-catenin is well documented in cancer cells, thereby linking b-catenin signaling and cell migration induced by growth factors.…”

“…22 FoxM1 promotes b-catenin nuclear accumulation and together they form a complex with TCF4 required for glioma stem cell self-renewal and gliomagenesis. 22,23 Crosstalk between EGFR, c-Met and Wnt/b-catenin is well documented in cancer cells, thereby linking b-catenin signaling and cell migration induced by growth factors. [24][25][26][27][28][29] Thus, stimulation of epithelial cells with EGF or HGF through the phosphorylation of cell adhesion proteins diminishes cell adhesion while promoting epithelial-mesenchymal transition (EMT).…”

Therapeutic Innovations for Targeting Hepatoblastoma

“…Disruption of this complex could, therefore, be the cause of Wnt inhibition in Wnt-dependent cancer cells leading to enhanced susceptibility for apoptosis and growth arrest. In accordance, Zhang et al showed that FOXM1 mutation or nuclear import prevented β-catenin nuclear accumulation in tumor cells, which led to a decrease in Wnt activity (134). Nevertheless, these findings do not explain how exactly β-catenin accumulates at the membrane.…”

The dual role of N6‐methyladenosine modification of RNAs is involved in human cancers

“…In terms of glioblastoma, inactivated ALKBH5 inhibited the proliferation and tumorigenesis of GSCs and impaired GSCs self‐renewal 75. It is widely accepted that FOXM1 plays a pivotal role in regulating GSCs proliferation and self‐renewal 76, 77. ALKBH5 was found to demethylate FOXM1 nascent transcripts and promote FOXM1 expression, whereas long non‐coding RNA antisense of FOXM1 further promoted the interaction of FOXM1 nascent transcripts with ALKBH5.…”