RGS6 Suppresses Cellular Transformation by Oncogenic Ras Through a Tip60‐Dnmt1‐apoptosis Dependent Mechanism (609.14)

Silencing of tumor suppressor genes by DNA methyltransferase 1 (Dnmt1), dysregulated in human cancers, is essential for oncogenic transformation by the Ras protooncogene. Here, we provide evidence that Regulator of G protein Signaling 6 (RGS6) suppresses Ras‐induced cellular transformation by facilitating Tip60‐mediated Dnmt1 degradation and promoting apoptosis. Employing mouse embryonic fibroblasts (MEFs) from wild type (WT) and RGS6 ‐/‐ mice, we found that Ras induced up‐regulation of RGS6, which in turn blocked Ras‐induced cellular transformation. RGS6 suppresses cellular transformation by down regulating Dnmt1 leading to inhibition of Dnmt1‐mediated anti‐apoptotic activity. Further experiments showed that RGS6 is a scaffolding protein for Dnmt1 and Tip60 required for Tip60‐mediated acetylation of Dnmt1 and Dnmt1 ubiquitylation and degradation. Indeed, RGS6 loss promotes Dnmt1 up‐regulation in a mouse model of breast cancer possibly contributing to accelerated tumorigenesis observed in RGS6 ‐/‐ mice. This work demonstrates a novel signaling action for RGS6 in negative regulation of oncogenesis providing new insights into our understanding of the mechanisms regulating Ras‐induced cellular transformation and Dnmt1 expression. Importantly, these findings identify RGS6 as an essential cellular defender against oncogenic stress and a potential therapeutic target in cancer treatment. Grant Funding Source : Supported by NCI CA161882 (RAF), HHSN261200433000C (CB), CA090367 (DEQ)