Suberoylanilide hydroxamic acid (SAHA; vorinostat) suppresses translation of cyclin D1 in mantle cell lymphoma cells

Mantle cell lymphoma (MCL) has a chromosomal translocation resulting in the expression of the cyclin D1 gene driven by the powerful enhancer of the immunoglobulin heavy chain gene, leading to uncontrolled, overexpressed cyclin D1 protein. We showed that suberoylanilide hydroxamic acid (SAHA; vorinostat), one of the histone deacetylase inhibitors derived from hydroxamic acid, caused a dramatic decrease (90%) in protein levels of cyclin D1 after 8-hour exposure to SAHA (5 muM) in MCL lines (SP49, SP53, Jeko1). mRNA levels and protein stability of cyclin D1 were minimally affected by SAHA over 8 hours. In contrast, metabolic labeling assays showed that SAHA decreased incorporation of (35)S]methionine into cyclin D1 protein. The drug also decreased levels of phosphorylated Akt, mammalian target of Rapamycin (mTOR), and eukaryotic translation initiation factor 4E binding protein (eIF4E-BP) and lowered the cap site binding activity of eIF4E in the MCL cells. In vitro phosphatidyl inositol (PI) kinase assay demonstrated that SAHA directly inhibited kinase activity of PI 3' kinase. Taken together, SAHA caused a rapid decrease of cyclin D1 in MCL by blocking the translation of cyclin D1 by inhibiting the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR/eIF4E-BP pathway, probably by PI3K inhibition.