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

?-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.
Mesh Terms:
Acetylation, Autophagy, Catenins, Cell Line, Tumor, Down-Regulation, HEK293 Cells, Humans, Male, Prostatic Neoplasms, Proteolysis, Up-Regulation, p300-CBP Transcription Factors
Sci Rep
Date: Dec. 04, 2018
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