p27^Kip1 that regulates the G1/S transition of cell cycle and inhibits Rho A signaling is frequently lost in several cancers leading to the deregulation of cell growth and cell motility. Mitogen‐activated protein kinases (MAPK) regulate the export of p27^Kip1 from nucleus to cytoplasm, followed by the degradation with proteases. Skp‐2, a subunit of an SCF ubiquitin‐protein ligase complex responsible for the ubiquitination of p27^Kip1, is upregulated frequently in several cancers, leading to the decrease of p27^Kip1. We applied human immunodeficiency virus (HIV) lentivirus‐mediated RNA interference (RNAi) to melanoma cells with the BRAF mutation (V599E) and overexpressed Skp‐2 and found that the simultaneous suppression of these activated oncogenes resulted in the effective inhibition of in vitro cell growth and invasive ability of melanoma cells accompanied by the additional increase of p27^Kip1. Our results suggest that gene therapy against melanoma with the enhanced MAPK and ubiquitin‐proteasomal pathways could be a specific and effective therapeutic strategy for cancers. © 2005 Wiley‐Liss, Inc.