Id1 and Id3 expression is associated with increasing grade of prostate cancer: Id3 preferentially regulates CDKN1B

Abstract

As transcriptional regulators of basic helix–oop–helix (bHLH) transcription and non-bHLH factors, the inhibitor of differentiation (Id1, Id2, Id3, and Id4) proteins play a critical role in coordinated regulation of cell growth, differentiation, tumorigenesis, and angiogenesis. Id1 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 Id2 and Id3 in PCa progression. In this study we investigated the expression of Id2 and Id3 and reevaluated the expression of Id1 in PCa. We show that increased Id1 and Id3 protein expression is strongly associated with increasing grade of PCa. At the molecular level, we report that silencing either Id1 or Id3 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 Id1 and Id3 primarily attenuates CDKN1A (p21) and CDKN1B (p27), respectively. We also demonstrate that silencing Id3 alone significantly attenuates proliferation of PCa cells as compared with Id1. We propose that increased Id1 and Id3 expression attenuates all three cyclin-dependent kinase inhibitors (CDKN2B, -1A, and -1B) resulting in a more aggressive PCa phenotype.

Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling

“…We identified a strong candidate for this role, inhibitor of differentiation 1 ( ID1 ), which was upregulated in LNCaP APIPC compared with LNCaP shAR/pATK (∼10-fold by RNA-seq; q < 0.001; 5-fold byqRT-PCR) (Figure 7A). ID1 expression is induced by exogenous FGF and bone morphogenetic protein via MAPK pathway activation (Langenfeld and Langenfeld, 2004; Passiatore et al, 2011), prevents differentiation by binding cell lineage-specific transcription factors (Perk et al, 2005), and has been associated with poorly differentiated PC (Coppe et al, 2004; Sharma et al, 2012). Notably, other ID family members were also increased in LNCaP APIPC and the LuCaP173.2 DNPC PDX (Figure 7B).…”

Intra-tumoral delivery of functional ID4 protein via PCL/maltodextrin nano-particle inhibits prostate cancer growth

“…Multiple studies have shown that increased ID1 expression in PCa [12] is associated with castration resistance and resistance to chemotherapeutic agents [43–45]. Since ID4 lacks a DNA binding domain hence most of its regulatory actions may involve interactions with other proteins.…”

Inhibitor of differentiation 4 (ID4) acts as an inhibitor of ID-1, -2 and -3 and promotes basic helix loop helix (bHLH) E47 DNA binding and transcriptional activity

“…After incubation with primary and secondary antibodies, the membranes were developed using an ECL kit (GE Life Sciences, Piscataway, NJ) as described earlier 51 . The ID-1, -2, -3, -4 and E47 antibodies used in this study have been validated as described in our previous studies 51–53 .…”