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.

SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination SKP2 inactivation suppresses prostate tumorigenesis by mediating JARID1B ubiquitination

The initiation and progression of human prostate cancer are highly associated with aberrant dysregulations of tumor suppressors and proto-oncogenes. Despite that deletions and mutations of tumor suppressors and aberrant elevations of oncogenes at the genetic level are reported to cause cancers, emerging evidence has revealed that cancer progression is largely regulated by posttranslational modifications (PTMs) and epigenetic alterations. PTMs play critical roles in gene regulation, cellular functions, tissue development, diseases, malignant progression and drug resistance. Recent discoveries demonstrate that ubiquitination and SUMOylation are complicated but highly-regulated PTMs, and make essential contributions to diseases and cancers by regulation of key factors and signaling pathways. Ubiquitination and SUMOylation pathways can be differentially modulated under various stimuli or stresses in order to produce the sustained oncogenic potentials. In this review, we discuss some new insights about molecular mechanisms on ubiquitination and SUMOylation, their associations with diseases, oncogenic impact on prostate cancer (PCa) and clinical implications for PCa treatment.

KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer. KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to prostate cancer tumorigenesis remain unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and prostate cancer progression in cultured cells and in mouse models of prostate epithelium–specific mutant Pten/Kdm5b. Kdm5b deficiency resulted in a significant delay in the onset of prostate cancer in Pten-null mice, whereas Kdm5b loss alone caused no morphologic abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared with that of Pten mice. Pathologic analysis revealed Pten/Kdm5b mice displayed mild morphologic changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high-grade prostatic intraepithelial neoplasia and prostate cancer. Mechanistically, KDM5B governed PI3K/AKT signaling in prostate cancer in vitro and in vivo. KDM5B directly bound the PIK3CA promoter, and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human prostate cancer cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against prostate cancer. Significance: This study demonstrates that levels of histone modification enzyme KDM5B determine hyperactivation of PI3K/AKT signaling in prostate cancer and that targeting KDM5B could be a novel strategy against prostate cancer.