Inhibition of the 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase Pathway Induces p53-independent Transcriptional Regulation of p21WAF1/CIP1 in Human Prostate Carcinoma Cells

• Published in: The Journal of biological chemistry Vol. 273; no. 17; pp. 10618 - 10623
• Main Authors: Lee, Su Jae, Ha, Mahn Joon, Lee, Jeen, Nguyen, PhuongMai, Choi, Yung Hyun, Pirnia, Farzaneh, Kang, Won-Ki, Wang, Xiao-Fan, Kim, Seong-Jin, Trepel, Jane B.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 24.04.1998
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.273.17.10618

Progression through the cell cycle is controlled by the induction of cyclins and the activation of cognate cyclin-dependent kinases. The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovastatin induces growth arrest and cell death in certain cancer cell types. We have pursued the mechanism of growth arrest in PC-3-M cells, a p53-null human prostate carcinoma cell line. Lovastatin treatment increased protein and mRNA levels of the cyclin-dependent kinase inhibitor p21WAF1/CIP1, increased binding of p21 with Cdk2, markedly inhibited cyclin E- and Cdk2-associated phosphorylation of histone H1 or GST-retinoblastoma protein, enhanced binding of the retinoblastoma protein to the transcription factor E2F-1 in vivo, and induced the activation of a p21 promoter reporter construct. By using p21 promoter deletion constructs, the lovastatin-responsive element was mapped to a region between −93 and −64 relative to the transcription start site. Promoter mutation analysis indicated that the lovastatin-responsive site coincided with the previously identified transforming growth factor-β-responsive element. These data indicate that in human prostate carcinoma cells an inhibitor of the HMG-CoA reductase pathway can circumvent the loss of wild-type p53 function and induce critical downstream regulatory events leading to transcriptional activation of p21.