Id 1 and Id 3 expression is associated with increasing grade of prostate cancer: Id 3 preferentially regulates CDKN 1B

As transcriptional regulators of basic helix–oop–helix ( bHLH ) transcription and non‐ bHLH factors, the inhibitor of differentiation ( Id 1, Id 2, Id 3, and Id 4) proteins play a critical role in coordinated regulation of cell growth, differentiation, tumorigenesis, and angiogenesis. Id 1 regulates prostate cancer ( PCa ) cell proliferation, apoptosis, and androgen independence, but its clinical significance in PCa remains controversial. Moreover, there is lack of evidence on the expression of Id 2 and Id 3 in PCa progression. In this study we investigated the expression of Id 2 and Id 3 and reevaluated the expression of Id 1 in PCa . We show that increased Id 1 and Id 3 protein expression is strongly associated with increasing grade of PCa . At the molecular level, we report that silencing either Id 1 or Id 3 attenuates cell cycle. Although structurally and mechanistically similar, our results show that both these proteins are noncompensatory at least in PCa progression. Moreover, through gene silencing approaches we show that Id 1 and Id 3 primarily attenuates CDKN 1A (p21) and CDKN 1B (p27), respectively. We also demonstrate that silencing Id 3 alone significantly attenuates proliferation of PCa cells as compared with Id 1. We propose that increased Id 1 and Id 3 expression attenuates all three cyclin‐dependent kinase inhibitors ( CDKN 2B, ‐1A, and ‐1B) resulting in a more aggressive PCa phenotype.