Inhibition of Methyltransferases Results in Induction of G 2 /M Checkpoint and Programmed Cell Death in Human T-Lymphotropic Virus Type 1-Transformed Cells

Human T-lymphotropic virus type 1 (HTLV-1) is the etiologic agent for adult T-cell leukemia. The HTLV-1-encoded protein Tax transactivates the viral long terminal repeat and plays a critical role in virus replication and transformation. Previous work from our laboratory demonstrated that coactivator-associated arginine methytransferase 1, a protein arginine methytransferase, was important for Tax-mediated transactivation. To further investigate the role of methyltransferases in viral transcription, we utilized adenosine-2,3-dialdehyde (AdOx), an adenosine analog andS -adenosylmethionine-dependent methyltransferase inhibitor. The addition of AdOx decreased Tax transactivation in C81, Hut102, and MT-2 cells. Unexpectedly, we found that AdOx potently inhibited the growth of HTLV-1-transformed cells. Further investigation revealed that AdOx inhibited the Tax-activated NF-κB pathway, resulting in reactivation of p53 and induction of p53 target genes. Analysis of the NF-κB pathway demonstrated that AdOx treatment resulted in degradation of the IκB kinase complex and inhibition of NF-κB through stabilization of the NF-κB inhibitor IκBα. Our data further demonstrated that AdOx induced G2 /M cell cycle arrest and cell death in HTLV-1-transformed but not control lymphocytes. These studies demonstrate that protein methylation plays an important role in NF-κB activation and survival of HTLV-1-transformed cells.