REST and diabetes mellitus: Recently, the use of pioglitazone for type 2 diabetes mellitus is reportedly associated with an increased risk of bladder cancer [53], suggesting a context-dependent, bidirectional effect of PPARγ on tumorigenesis, which is in accordance with its cell-specific effect on E3 skipping (Fig.5), as well as the notion that both decreased and increased REST activity may contribute to tumorigenesis [18], [19].