Restoring PML tumor suppression to combat cancer

Surmounting multiple tumor suppressive barriers is fundamental to cancer onset, but also predicts that their restoration may pose a powerful anticancer strategy. The proof of this principle has been elegantly demonstrated by the restoration of p53-induced tumor suppression (reviewed in ref. 1). The promyelocytic leukemia protein (PML) is emerging as a key tumor suppressor that is inactivated in multiple cancer types and is thus a candidate for therapeutic restoration. PML is the indispensable component of PML nuclear bodies, which are structures that coalesce in response to cellular stress and are implicated in growth inhibitory functions. Three important criteria distinguish PML as an attractive candidate for tumor suppression. First, PML inhibits the growth of tumor cells by regulating multiple pathways, including those activating the p53 family and inhibiting the PI3K/AKT pathway. Further, PML has been substantiated to inhibit tumor development in various mouse models. Second, PML expression is frequently downregulated or lost in a wide spectrum of human cancers, including prostate adenocarcinoma, B-lymphoma, lung, colon and breast adenocarcinomas. Third, PML is rarely mutated, and its downregulation occurs predominantly at the post-translational level. These criteria render PML as a promising candidate for restoration of tumor suppression, and intense research has been directed toward delineating its regulation at the posttranslational level. These studies revealed that the stability of PML is regulated by multiple mechanisms (Fig. 1) including phosphorylation (by Caseine Kinase 2, Restoring PML tumor suppression to combat cancer