The tumor suppressor ING1b is a novel corepressor for the androgen receptor and induces cellular senescence in prostate cancer cells.

The androgen receptor (AR) signaling is critical for prostate cancer (PCa) progression to the castration-resistant stage with poor clinical outcome. Altered function of AR-interacting factors may contribute to castration-resistant PCa (CRPCa). Inhibitor of growth 1 (ING1) is a tumor suppressor that regulates various cellular processes including cell proliferation. Interestingly, ING1 expression is upregulated in senescent primary human prostate cells; however, its role in AR signaling in PCa was unknown. Using a proteomic approach by surface-enhanced laser desorption ionization-mass spectrometry (SELDI-MS) combined with immunological techniques, we provide here evidence that ING1b interacts in vivo with the AR. The interaction was confirmed by co-immunoprecipitation, in vitro GST-pull-down, and quantitative intracellular colocalization analyses. Functionally, ING1b inhibits AR-responsive promoters and endogenous key AR target genes in the human PCa LNCaP cells. Conversely, ING1b knockout (KO) mouse embryonic fibroblasts (MEFs) exhibit enhanced AR activity, suggesting that the interaction with ING1b represses the AR-mediated transcription. Also, data suggest that ING1b expression is downregulated in CRPCa cells compared with androgen-dependent LNCaP cells. Interestingly, its ectopic expression induces cellular senescence and reduces cell migration in both androgen-dependent and CRPCa cells. Intriguingly, ING1b can also inhibit androgen-induced growth in LNCaP cells in a similar manner as AR antagonists. Moreover, ING1b upregulates different cell cycle inhibitors including p27(KIP1), which is a novel target for ING1b. Taken together, our findings reveal a novel corepressor function of ING1b on various AR functions, thereby inhibiting PCa cell growth.

Esmaeili M ，Jennek S ，Ludwig S ，Klitzsch A ，Kraft F ，Melle C ，Baniahmad A ... -  《-》

A novel crosstalk between the tumor suppressors ING1 and ING2 regulates androgen receptor signaling.

Esmaeili M ，Pungsrinont T ，Schaefer A ，Baniahmad A ... -  《-》

A natural androgen receptor antagonist induces cellular senescence in prostate cancer cells.

Hessenkemper W ，Roediger J ，Bartsch S ，Houtsmuller AB ，van Royen ME ，Petersen I ，Grimm MO ，Baniahmad A ... -  《-》

Inhibition of MAPK-signaling pathway promotes the interaction of the corepressor SMRT with the human androgen receptor and mediates repression of prostate cancer cell growth in the presence of antiandrogens.

Eisold M ，Asim M ，Eskelinen H ，Linke T ，Baniahmad A ... -  《-》

The tumor suppressor p33ING1b upregulates p16INK4a expression and induces cellular senescence.

ING1 protein is a tumor suppressor which plays significant roles in multiple cellular activities. p47(ING1a) and p33(ING1b) are major splice isoforms of ING1 and their roles in senescence need further investigations. Here we studied the functions of ING1 isoforms in cellular senescence and gene regulation, with focus on p16(INK4a). We observe that p33(ING1b) protein is the major ING1 isoform expressed in 2BS human diploid fibroblasts. Overexpression of p33(ING1b) induces cellular senescence and upregulates p16(INK4a) expression in 2BS fibroblasts. p33(ING1b) upregulates p16(INK4a) transcription. p33(ING1b) and p300 bind to the p16(INK4a) promoter. p300/CBP-specific inhibitor curcumin can reverse the induction of p16(INK4a) by p33(ING1b). These results help to better understand the function of ING1.

Li N ，Li Q ，Cao X ，Zhao G ，Xue L ，Tong T ... -  《-》