PCAF Acts As A Gastric Cancer Suppressor Through A Novel PCAF-p16-CDK4 Axis

P300/CBP-associated factor(PCAF)is a member of the histone acetyltransferases(HATs)consists of ubiquitin E3 ligase domain and the acetyltransferase domain.As an ubiquitin-modifying enzyme,PCAF promote the ubiquitin-dependent proteasomal degradation through its intrinsic E3 ligase activity.As a histone acetyltransferase,PCAF not only acetylated free histones and histones in nucleosomes,but also acetylated nonhistones such as p53,E2F1,MyoD and so on.Anion exchanger-1(AE1),an erythroid-specific membraneprotein,specifically expressed in erythrocyte membrane under normal physiological condition,mediates the Cl-/HCO3-exchange across the plasma membrane and regulates intracellular pH.We have previously documented that AE1 interacted with tumor suppressor p16 in the cytoplasm of GC cells that leads to degradation of AE2,disorder of gastric acid secretion and cytoplasmic sequestrate of p16.Thus,unexpected expression of AE1 and p16 is involved in GC progression.Here,we show that PCAF is downregulated in poorly differentiated GC cells.Overexpression of PCAF arrested the GC cells in G1/S phase,and significantly inhibits the proliferation of the cells.The histological analysis of GC tissue microarrays further confirmed that lower PCAF expression levels correlated with poor differentiation and higher GC grade.The above results suggested that loss of PCAF function is associated with poor prognosis of GC patients and PCAF acts as a cancer suppressor in GC.Further experiments demonstrated that PCAF inhibited GC growth by interacting with AE1 and p16 to promote ubiquitin-mediated degradation of AE1,translocation of p16 into the nucleus and re-establishment of PCAF-p16-CDK4 axis.Binding of nuclear p16 to CDK4 prevented the CDK4-Cyclin D1 interaction to inhibit GC proliferation.Once p16 was knocked out,the effect of PCAF on GC would be weakened.Together these results suggest that PCAF acts as a GC suppressor through a novel PCAF-p16-CDK4 axis.Furthermore,reduction of PCAF in GC cells is associated with intracellular alkalization and decreased immunity and GC therapies should focus on restoring PCAF levels.