Vps34, a class III PtdIns3
lipid kinase involved in the control of both autophagic and endocytic systems, has been studied extensively in numerous fundamental cellular processes. Accumulating evidence indicates that Vps34 may also contribute to the development and progression of human
cancers. However, the mechanism of Vps34 in
tumorigenesis remains elusive. Here, we report an unanticipated role of Vps34 in the activation of p62 for
cancer development. We identified that Vps34 is a transcriptional activator of p62 through competition of Nrf2 (nuclear factor erythroid 2-related factor 2) for Keap1 binding. Vps34 augments the association of PKC-δ with p62 for its phosphorylation at
Serine 349, which leads to positive feedback on the Nrf2-dependent transcription of oncogenes. Additionally, we found that the expression of Vps34 is correlated with the tumorigenic activity of human
breast cancer cells. Normally inactive in
breast cancer,
caspase 8 can cleave Vps34 at residue D285, which directly abolished its
lipid kinase activity and dramatically altered cell invasion potential, colony formation, as well as
tumorigenesis in orthotopic engraftments in mice. The cleavage at D285 blocks expression of LC3-II, Nrf2 and subsequently, p62, in addition to blocking
tumor growth, indicating that the intact structure of Vps34 is essential for its activity. Moreover, either knockout of PKC-δ or knockdown of p62 by
small interfering RNA in MCF-7 cells abrogates Vps34-dependent
tumor growth. Data presented here suggested that Vps34 stimulates
tumor development mainly through PKC-δ- activation of p62.