Upregulation of Twist-1 by NF-κB blocks cytotoxicity induced by chemotherapeutic drugs

NF-kappa B/Rel transcription factors are central to controlling programmed cell death (PCD). Activation of NF-kappa B blocks PCD induced by numerous triggers, including ligand engagement of tumor necrosis factor receptor (TNF-R) family receptors. The protective activity of NF-kappa B is also crucial for oncogenesis and cancer chemoresistance. Downstream of TNF-Rs, this activity of NF-kappa B has been linked to the suppression of reactive oxygen species and the c-Jun-N-terminal-kinase (JNK) cascade. The mechanism by which NF-kappa B inhibits PCD triggered by chemotherapeutic drugs, however, remains poorly understood. To understand this mechanism, we sought to identify unrecognized protective genes that are regulated by NF-kappa B. Using an unbiased screen, we identified the basic-helix-loop-helix factor Twist-1 as a new mediator of the protective function of NF-kappa B. Twist-1 is an evolutionarily conserved target of NF-kappa B, blocks PCD induced by chemotherapeutic drugs and TNF-alpha in NF-kappa B-deficient cells, and is essential to counter this PCD in cancer cells. The protective activity of Twist-1 seemingly halts PCD independently of interference with cytotoxic JNK, p53, and p19(ARF) signaling, suggesting that it mediates a novel protective mechanism activated by NF-kappa B. Indeed, our data indicate that this activity involves a control of inhibitory Bcl-2 phosphorylation. The data also suggest that Twist-1 and -2 play an important role in NF-kappa B-dependent chemoresistance.