p300/CBP-associated factor promotes autophagic degradation of δ-catenin through acetylation and decreases prostate cancer tumorigenicity

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