Slug regulates E-cadherin repression via p19Arf in prostate tumorigenesis

SLUG represses E-cadherin to promote epithelial–mesenchymal transition (EMT) in various cancers. Mechanisms that regulate SLUG/E-cadherin pathway remain poorly understood, especially during tumorigenesis in vivo. Here we report that p19Arf (p14ARF in human) stabilizes Slug to inhibit E-cadherin in prostate cancer mouse models. Inactivation of p19Arf reduces Slug levels, resulting in increased E-cadherin expression and delaying the onset and progression of prostate cancer in Pten/Trp53 double null mice. Mechanistically, p14ARF stabilizes SLUG through increased sumoylation at lysine residue 192. Importantly, levels of SLUG and p14ARF are positively correlated in human prostate cancer specimens. These data demonstrated that ARF modulates the SLUG/E-cadherin signaling axis for augmenting prostate tumorigenesis in vivo, revealing a novel paradigm where the oncogenic functions of SLUG require ARF to target E-cadherin in prostate cancer. Collectively, our findings further support that ARF has dual tumor suppressive/oncogenic roles in cancers in a context-dependent manner. •p19Arf deficiency inhibits prostate tumorigenesis of Pten/Trp53 mice.•p19Arf inactivation results in Slug decrease and E-cadherin increase in vivo.•ARF stabilizes SLUG through SUMO1 interaction.•SLUG sumoylation at K192 residue is essential for the stability.•Levels of SLUG and ARF are positively correlated in human prostate cancer specimens.