Roles of the Polycomb group proteins in stem cells and cancer

Abstract

Polycomb group proteins have long been linked to the occurrence of different forms of cancer. Polycomb proteins form at least two distinct complexes, the Polycomb-repressive complexes 1 and 2 (PRC1 and PRC2). Some of the PRC complex subunits have been found to be overexpressed in a variety of different tumors. Epigenetic perturbations are likely to be the cause for transcriptional misregulation of tumor suppressor genes and of certain cell fates. It is especially critical for stem cells that their potential to self-renewal and to differentiate is tightly controlled and properly orchestrated. Misregulation of Polycomb protein levels often leads to either a block or unscheduled activation of developmental pathways, thereby enhancing the proliferation capability of a cell. The consequences of this misregulation have been linked to the establishment of cancer stem cells, which can produce tumors through a combination of increased self-renewal and the lack of complete cellular differentiation. Cancer stem cells are believed to persist within tumors and to elicit relapse and metastasis. In this review, we recapitulate the roles of Polycomb proteins in stem cell biology, and the impact their misregulation can have on cancer.

Figure 1

Epigenetic modifications at bivalent genes. Bivalent genes are earmarked by activating and repressive epigenetic marks. MLL complexes decorate chromatin with an activating H3K4me3 mark. The consecutive action of PRC2 and PRC1 complexes leads to disposition of repressive marks at chromatin. PRC2 carries out the specific methylation (H3K27me3), which is thought to recruit PRC1 via proteins of the CBX family. PRC1 complexes subsequently transfer a monoubiquitin residue to histone H2A (H2AK119). Both, PRC1 and monoubiquitinated histone H2A (H2Aub) lock chromatin in a silenced state and force Pol II to remain in a paused state

Figure 2

Role of Polycomb proteins in the emergence of cancer stem cells. ES cells undergo asymmetric cell divisions that give rise to daughter cells (self-renewal) and progenitor cells that ultimately differentiate into a distinct cell type. Integrity of Polycomb complexes is required for proper ES and adult stem cell differentiation. In addition, PRC1 and PRC2 are required for the self-renewal of adult, but not embryonic, stem cells. Misregulation of the levels of the Polycomb group proteins can lead to the formation of cancer stem cells, which maintain the ability to self-renew and undergo uncontrolled differentiation, leading to the generation of heterogenous tumors