INHIBITION OF THE 3-HYDROXY-3-METHYLGLUTARYL-COENZYME-A REDUCTASE PATHWAY INDUCES P53-INDEPENDENT TRANSCRIPTIONAL REGULATION OF P21(WAF1 CIP1) IN HUMAN PROSTATE CARCINOMA-CELLS/

Progression through the cell cycle is controlled by the induction of c yclins and the activation of cognate cyclin-dependent kinases. The 3-h ydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor lovas tatin induces growth arrest and cell death in certain cancer cell type s. We have pursued the mechanism of growth arrest in PC-3-M cells, a p 53-null human prostate carcinoma cell line. Lovastatin treatment incre ased protein and mRNA levels of the cyclin-dependent kinase inhibitor p21(WAF1/CIP1), increased binding of p21 with Cdk2, markedly inhibited cyclin E-and Cdk2-associated phosphorylation of histone H1 or GST-ret inoblastoma 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 con structs, the lovastatin-responsive element was mapped to a region betw een -93 and -64 relative to the transcription start site. Promoter mut ation analysis indicated that the lovastatin-responsive site coincided with the previously identified transforming growth factor-beta-respon sive element. These data indicate that in human prostate carcinoma cel ls an inhibitor of the HMG-CoA reductase pathway can circumvent the lo ss of wild-type p53 function and induce critical downstream regulatory events leading to transcriptional activation of p21.