Id1 and Id3 expression is associated with increasing grade of prostate cancer: Id3 preferentially regulates CDKN1B.
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.
Department of Biological Sciences, Centre for Cancer Research and Therapeutics Development, Clark Atlanta University, Atlanta, Georgia, 30314, USA.
Pankaj
P
Sharma
Divya
D
Patel
Jaideep
J
Chaudhary
D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000096:biosynthesis* / Q000235:genetics; D051797:Inhibitor of Differentiation Protein 2 / Q000096:biosynthesis* / Q000235:genetics; D051796:Inhibitor of Differentiation Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D060787:Neoplasm Grading; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D034622:RNA Interference; D034741:RNA, Small Interfering
C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004268:DNA-Binding Proteins; C497453:ID1 protein, human; C497450:ID2 protein, human; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D050760:Cyclin-Dependent Kinase Inhibitor p27; C075640:ID3 protein, human
Id1; Id2; Id3; inhibitor of differentiation; prostate cancer