INAUGURAL ARTICLE by a Recently Elected Academy Member: Loss of the retinoblastoma binding protein 2 (RBP2) histone demethylase suppresses tumorigenesis in mice lacking Rb1 or Men1

Epigenetic alterations, like genetic alterations, can contribute to tumor initiation and progression (1, 2). Indeed, a number of genes that play roles in chromatin modifications and hence, epigenetic regulation are mutated in human cancers, including mixed-lineage leukemia (MLL1), multiple endocrine neoplasia type 1 (MEN1), and ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX) (3–6).\r\n\r\nThe retinoblastoma gene (RB1) tumor suppressor gene is frequently inactivated in a wide variety of cancers (7). The retinoblastoma protein (pRB) inhibits S-phase entry by repressing E2F (7). In addition, pRB promotes senescence and differentiation (8). These latter two activities track closely with the ability of pRB to bind to retinoblastoma binding protein 2 (RBP2; also called JARID1A or KDM5A) rather than to E2F (9). Moreover, RBP2 siRNA is sufficient to promote senescence and differentiation in pRB-defective tumor cells in vitro (9, 10). RBP2 is a histone demethylase capable of demethylating tri- and dimethylated lysine 4 in histone H3 (H3K4me3/2) and repressing gene expression (11–14). It is, therefore, conceivable that deregulation of RBP2 histone demethylase activity contributes to pRB-defective tumor formation.\r\n\r\nEpigenetic changes are reversible, suggesting that inhibition of specific enzymes that regulate epigenetic marks would have antitumor effects. In fact, suberoylanilide hydroxamic acid (vorinostat), a histone deacetylase (HDAC) inhibitor, was approved for the treatment of cutaneous T-cell lymphoma (15), and two DNA methyltransferase inhibitors, 5-azacytidine (azacitidine) and 5-aza-2′-deoxycytidine (decitabine), were approved for the treatment of myelodysplastic syndrome (16, 17). RBP2 belongs to a superfamily of 2-oxoglutarate–dependent dioxygenases (18, 19), which can be inhibited with drug-like small molecules (20, 21). We, therefore, used mice carrying null or conditional Rbp2 alleles to further explore potential roles for RBP2 in pRB-defective tumorigenesis. In addition, we tested the hypothesis that loss of RBP2 H3K4 demethylase activity would inhibit tumors driven by loss of the MEN1 tumor suppressor, which is part of an H3K4 methyltransferase complex (6, 22, 23).