Activation of forkhead box O transcription factors by oncogenic BRAF promotes p21cip1-dependent senescence.

Oncogene-induced senescence (OIS) is a potent tumor-suppressive mechanism that is thought to come at the cost of aging. The Forkhead box O (FOXO) transcription factors are regulators of life span and tumor suppression. However, whether and how FOXOs function in OIS have been unclear. Here, we show a role for FOXO4 in mediating senescence by the human BRAF V600E oncogene, which arises commonly in melanoma. BRAF V600E signaling through mitogen-activated protein kinase/extracellular signal-regulated kinase kinase resulted in increased reactive oxygen species levels and c-Jun NH 2 terminal kinase–mediated activation of FOXO4 via its phosphorylation on Thr 223 , Ser 226 , Thr 447 , and Thr 451 . BRAF V600E -induced FOXO4 phosphorylation resulted in p21 cip1 -mediated cell senescence independent of p16 ink4a or p27 kip1 . Importantly, melanocyte-specific activation of BRAF V600E in vivo resulted in the formation of skin nevi expressing Thr 223 /Ser 226 -phosphorylated FOXO4 and elevated p21 cip1 . Together, these findings support a model in which FOXOs mediate a trade-off between cancer and aging. Cancer Res; 70(21); 8526–36. ©2010 AACR.