Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase

Significance Developing therapeutic strategies for tumors driven by tumor suppressor gene inactivation, as opposed to oncogene activation, represents a significant challenge in oncology. While restoration of tumor suppressor functionality is generally not feasible, inhibiting proteins that act downstream of lost tumor suppressors represents one strategy to overcome this challenge. In this study, we applied this concept to the tumor suppressor generetinoblastoma 1 (RB1 ). TheRB1 gene product, pRB, associates with the RBP2 histone demethylase and RBP2 is deregulated inRB1 -null cancers. Here, we show that genetic ablation of RBP2 in established, autochthonous pRB-defective murine tumors retards their growth and enhances mouse survival. Our findings provide a further rationale for the development and testing of pharmacological RBP2 inhibitors for cancer treatment.