VHL loss in renal cell carcinoma leads to up-regulation of CUB domain-containing protein 1 to stimulate PKCδ-driven migration

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 5; pp. 1931 - 1936
• Main Authors: Razorenova, Olga V, Finger, Elizabeth C, Colavitti, Renata, Chernikova, Sophia B, Boiko, Alexander D, Chan, Charles K.F, Krieg, Adam, Bedogni, Barbara, LaGory, Edward, Weissman, Irving L, Broome-Powell, Marianne, Giaccia, Amato J
• Format: Journal Article
• Language: English
• Published: National Academy of Sciences 2011
• Subjects: adenocarcinoma; genes; kidney neoplasms; metastasis; mutation; neoplasm cells; non-specific protein-tyrosine kinase; patients; phosphorylation; prostatic neoplasms; protein kinase C; signal transduction
• ISSN: 0027-8424; 1091-6490

A common genetic mutation found in clear cell renal cell carcinoma (CC-RCC) is the loss of the von Hippel-Lindau (VHL) gene, which results in stabilization of hypoxia-inducible factors (HIFs), and contributes to cancer progression and metastasis. CUB-domain-containing protein 1 (CDCP1) was shown to promote metastasis in scirrhous and lung adenocarcinomas as well as in prostate cancer. In this study, we established a molecular mechanism linking VHL loss to induction of the CDCP1 gene through the HIF-1/2 pathway in renal cancer. Also, we report that Fyn, which forms a complex with CDCP1 and mediates its signaling to PKCδ, is a HIF-1 target gene. Mechanistically, we found that CDCP1 specifically regulates phosphorylation of PKCδ, but not of focal adhesion kinase or Crk-associated substrate. Signal transduction from CDCP1 to PKCδ leads to its activation, increasing migration of CC-RCC. Furthermore, patient survival can be stratified by CDCP1 expression at the cell surface of the tumor. Taken together, our data indicates that CDCP1 protein might serve as a therapeutic target for CC-RCC.