P300/CBP-associated factor promotes autophagic degradation of ?-catenin through acetylation and decreases prostate cancer tumorigenicity.

ABSTRACT: ?-Catenin shares common binding partners with ?-catenin. As acetylation and deacetylation regulate ?-catenin stability, we searched for histone acetyltransferases (HATs) or histone deacetylases (HDACs) affecting ?-catenin acetylation status and protein levels. We showed that p300/CBP-associated factor (PCAF) directly bound to and acetylated ?-catenin, whereas several class I and class II HDACs reversed this effect. Unlike ?-catenin, ?-catenin was downregulated by PCAF-mediated acetylation and upregulated by HDAC-mediated deacetylation. The HDAC inhibitor trichostatin A attenuated HDAC1-mediated ?-catenin upregulation, whereas HAT or autophagy inhibitors, but not proteasome inhibitors, abolished PCAF-mediated ?-catenin downregulation. The results suggested that PCAF-mediated ?-catenin acetylation promotes its autophagic degradation in an Atg5/LC3-dependent manner. Deletions or point mutations identified several lysine residues in different ?-catenin domains involved in PCAF-mediated ?-catenin downregulation. PCAF overexpression in prostate cancer cells markedly reduced ?-catenin levels and suppressed cell growth and motility. PCAF-mediated ?-catenin downregulation inhibited E-cadherin processing and decreased the nuclear distribution of ?-catenin, resulting in the suppression of ?-catenin/LEF-1-mediated downstream effectors. These data demonstrate that PCAF downregulates ?-catenin by promoting its autophagic degradation and suppresses ?-catenin-mediated oncogenic signals.

SUBMITTER: Zhou R 

PROVIDER: S-EPMC6399259 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature