Open AccessSlug regulates E‐cadherin repression via p19Arf in prostate tumorigenesis
Author(s) -
Xie Yingqiu,
Liu Shenji,
Lu Wenfu,
Yang Qing,
Williams Kieosha D.,
Binhazim Awadh A.,
Carver Brett S.,
Matusik Robert J.,
Chen Zhenbang
Publication year - 2014
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2014.05.006
Subject(s) - slug , carcinogenesis , prostate cancer , epithelial–mesenchymal transition , cancer research , cadherin , prostate , biology , pten , cancer , microbiology and biotechnology , signal transduction , pi3k/akt/mtor pathway , metastasis , genetics , cell
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.