Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers.

ABSTRACT: WNT-CTNN1B signaling promotes cancer cell proliferation and stemness. Furthermore, recent evidence indicates that macroautophagy/autophagy regulates WNT signaling. Here we investigated the impact of inhibiting WNT signaling on autophagy in glioblastoma (GBM), a devastating brain tumor. Inhibiting TCF, or silencing TCF4 or CTNNB1/β-catenin upregulated SQSTM1/p62 in GBM at transcriptional and protein levels and, in turn, autophagy. DKK1/Dickkopf1, a canonical WNT receptor antagonist, also induced autophagic flux. Importantly, TCF inhibition regulated autophagy through MTOR inhibition and dephosphorylation, and nuclear translocation of TFEB, a master regulator of lysosomal biogenesis and autophagy. TCF inhibition or silencing additionally affected GBM cell proliferation and migration. Autopha

SUBMITTER: Nager M 

PROVIDER: S-EPMC5959333 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature