Dual Role of SnoN in mammalian tumorigenesis

Department of Molecular and Cell Biology, University of California, Berkeley, and Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 USA; Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900

^* To whom correspondence should be addressed. Email: kluo{at}berkeley.edu.

	Abstract

SnoN is an important negative regulator of TGF signaling through its ability to interact with and repress the activity of Smad proteins. It was originally identified as an oncoprotein based on its ability to induce anchorage-independent growth in chicken embryo fibroblasts. However, the roles of SnoN in mammalian epithelial carcinogenesis have not been well defined. Here we show for the first time that SnoN plays an important but complex role in human cancer. SnoN expression is highly elevated in many human cancer cell lines, and this high level of SnoN promotes mitogenic transformation of breast and lung cancer cell lines in vitro and tumor growth in vivo, consistent with its proposed pro-oncogenic role. However, this high level of SnoN expression also inhibits epithelial to mesenchymal transdifferentiation. Breast and lung cancer cells expressing the shRNA for SnoN exhibited an increase in cell motility, actin stress fiber formation, metalloprotease activity and extracellular matrix production as well as a reduction in adherens junction proteins. Supporting this observation, in an in vivo breast cancer metastasis model, reducing SnoN expression was found to moderately enhance metastasis of human breast cancer cells to bone and lung. Thus, SnoN plays both pro-tumorigenic and anti-tumorigenic roles at different stages of mammalian malignant progression. The growth promoting activity of SnoN appears to require its ability to bind to and repress the Smad proteins, while the anti-tumorigenic activity can be mediated by both Smad-dependent and Smad-independent pathways and requires the activity of small GTPase RhoA. Our study has established the importance of SnoN in mammalian epithelial carcinogenesis and revealed a novel aspect of SnoN function in malignant progression.