Regulator of G protein Signaling 6 suppresses Ras and DNA‐methyltransferase 1 expression and tumorigenesis in a mouse model of urinary bladder cancer (609.10)

Urinary bladder cancer, the fifth most common cancer in the U.S., frequently results from exposure to toxic chemicals including those present in cigarette smoke. A previous epidemiological study demonstrated that a polymorphism in RGS6 leading to increased translation/stability of RGS6 mRNA was associated with a pronounced reduction in the risk of bladder cancer, particularly in smokers. However, no studies have evaluated whether RGS6 functions as a tumor suppressor in bladder. Here, we employed RGS6 ‐/‐ mice to investigate the role of RGS6 in BBN (N‐butyl‐N‐(4‐hydroxybutyl) nitrosamine)‐induced bladder cancer, a model which matches well to its human counterpart. We found that RGS6 was highly enriched in mouse bladder, particularly in urothelium where transitional cell carcinoma originates. RGS6 loss was associated with increases in Ras and Dnmt1 expression in the bladder urothelium and marked decreases in Ras‐association domain family 1 isoform A (RASSF1A), a tumor suppressor and target of Dnmt1‐mediated silencing. A similar phenomenon was observed in BBN‐treated WT mice, an effect further exacerbated by BBN treatment of RGS6 ‐/‐ mice. In keeping with these observations, RGS6 ‐/‐ mice exhibited accelerated bladder tumor formation. Our findings suggest that RGS6 is a previously unrecognized, but critical repressor for bladder carcinogenesis. Grant Funding Source : Supported by NIH CA161882, AHA 11SDG7580008