These authors contributed equally to this work.
SKI knockdown inhibits human melanoma tumor growth in vivo
Article first published online: 27 JUL 2009
© 2009 John Wiley & Sons A/S
Pigment Cell & Melanoma Research
Volume 22, Issue 6, pages 761–772, December 2009
How to Cite
Chen, D., Lin, Q., Box, N., Roop, D., Ishii, S., Matsuzaki, K., Fan, T., Hornyak, T. J., Reed, J. A., Stavnezer, E., Timchenko, N. A. and Medrano, E. E. (2009), SKI knockdown inhibits human melanoma tumor growth in vivo. Pigment Cell & Melanoma Research, 22: 761–772. doi: 10.1111/j.1755-148X.2009.00603.x
Annotation: SKI refers to the human protein; Ski to the mouse protein.
- Issue published online: 14 OCT 2009
- Article first published online: 27 JUL 2009
- PUBLICATION DATA Received 29 December 2008, revised and accepted for publication 29 June 2009
- SKI, TGF-β;
- Smad3 linker phosphorylation;
The SKI protein represses the TGF-β tumor suppressor pathway by associating with the Smad transcription factors. SKI is upregulated in human malignant melanoma tumors in a disease-progression manner and its overexpression promotes proliferation and migration of melanoma cells in vitro. The mechanisms by which SKI antagonizes TGF-β signaling in vivo have not been fully elucidated. Here we show that human melanoma cells in which endogenous SKI expression was knocked down by RNAi produced minimal orthotopic tumor xenograft nodules that displayed low mitotic rate and prominent apoptosis. These minute tumors exhibited critical signatures of active TGF-β signaling including high levels of nuclear Smad3 and p21Waf1, which are not found in the parental melanomas. To understand how SKI promotes tumor growth we used gain- and loss-of-function approaches and found that simultaneously to blocking the TGF-β-growth inhibitory pathway, SKI promotes the switch of Smad3 from tumor suppression to oncogenesis by favoring phosphorylations of the Smad3 linker region in melanoma cells but not in normal human melanocytes. In this context, SKI is required for preventing TGF-β-mediated downregulation of the oncogenic protein c-MYC, and for inducing the plasminogen activator inhibitor-1, a mediator of tumor growth and angiogenesis. Together, the results indicate that SKI exploits multiple regulatory levels of the TGF-β pathway and its deficiency restores TGF-β tumor suppressor and apoptotic activities in spite of the likely presence of oncogenic mutations in melanoma tumors.