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Review
. 2015 Nov;35(6):1220-67.
doi: 10.1002/med.21358. Epub 2015 Jul 30.

Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications

Wei Wang  1   2 , Jiang-Jiang Qin  1 , Sukesh Voruganti  1 , Subhasree Nag  1 , Jianwei Zhou  3 , Ruiwen Zhang  1   2
Affiliations
Review

Polycomb Group (PcG) Proteins and Human Cancers: Multifaceted Functions and Therapeutic Implications

Wei Wang et al. Med Res Rev. 2015 Nov.

Abstract

Polycomb group (PcG) proteins are transcriptional repressors that regulate several crucial developmental and physiological processes in the cell. More recently, they have been found to play important roles in human carcinogenesis and cancer development and progression. The deregulation and dysfunction of PcG proteins often lead to blocking or inappropriate activation of developmental pathways, enhancing cellular proliferation, inhibiting apoptosis, and increasing the cancer stem cell population. Genetic and molecular investigations of PcG proteins have long been focused on their PcG functions. However, PcG proteins have recently been shown to exert non-classical-Pc-functions, contributing to the regulation of diverse cellular functions. We and others have demonstrated that PcG proteins regulate the expression and function of several oncogenes and tumor suppressor genes in a PcG-independent manner, and PcG proteins are associated with the survival of patients with cancer. In this review, we summarize the recent advances in the research on PcG proteins, including both the Pc-repressive and non-classical-Pc-functions. We specifically focus on the mechanisms by which PcG proteins play roles in cancer initiation, development, and progression. Finally, we discuss the potential value of PcG proteins as molecular biomarkers for the diagnosis and prognosis of cancer, and as molecular _targets for cancer therapy.

Keywords: cancer, oncogene; polycomb group proteins; polycomb-repressive complex; tumor suppressor.

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Conflict of interest statement

Conflict of Interest: The authors disclose no potential conflicts of interest.

Figures

Figure 1
Figure 1. Epigenetic regulation of PcG proteins during differentiation and carcinogenesis
In embryonic stem cells (undifferentiated pluripotent cells), the genes crucial for development are marked by a specific ‘bivalent domain’ structure, composing of the active H3K4 methylation (H3K4me) and the repressive H3K27 trimethylation (H3K27me3) marks, which maintain the epigenomic plasticity. During differentiation, these bivalent domains transform into a more rigid ‘monovalent domain’ structures that is either active (with H3K4 methylation) or repressive (H2AK119 ubiquitination/H3K27 trimethylation), depending upon which mark is maintained. Based on the cell type, particular subsets of genes are expressed and silenced, ultimately leading to the generation of morphologically and functionally different cells. During cancer development and progression, both embryonic stem cells and differentiated cells undergo aberrant reprogramming of polycomb proteins that result in gene silencing through the formation of a compact chromatin structure. Silencing can occur through PRC reprogramming-silencing of active genes by the polycomb group, silencing through de novo hypermethylation, accompanied by H3K9 methylation (H3K9me).
Figure 2
Figure 2. Mechanisms of transcriptional silencing by PRCs
PRC1 complexes catalyze histone H2A lysine 119 (H2AK119Ub1) monoubiquitination. The catalytic subunits of PRC1 consist of RING1/2 and one of six PCGF protein homologues, PCGF1-6. PRC1 is typically involved in both the canonical and non-canonical pathways. Canonical PRC1 complexes contain RING1/2 ubiquitin ligase, PCGF2/4, the CBX subunit, and the PHC proteins. The association of additional subunits with non-canonical PRC1 occurs in a PCGF-dependent manner. Thus, PRC1 variant complexes include the additional subunits BCOR and KDM2B. PRC2 complexes consist of the catalytic EZH2 subunit and the core subunits EED, SUZ12, and RbAp48. The Jumonji C-containing protein, JARID2, binds to most PcG _target genes, and is itself required for the binding of PcGs to their _target genes in ES cells. However, JARID2 inhibition has minimal effects on the global H3K27me3 levels.
Figure 3
Figure 3. PcG protein recruitment to _target genes
(A) A high binding ratio between the homologous proteins Pho (P) and PhoI (PI) is seen at polycomb response elements (PREs), which is essential for _targeting and anchoring PRC2 and PRC1 to PREs. PcG protein complex recruitment to PREs occurs in conjunction with the previously identified PcG protein recruiters such as dorsal switch protein 1 (Dsp1), Pho, and Phol. In addition, non-coding RNAs (ncRNAs) help to recruit PcG protein complexes. The recruitment of PcG protein complexes to PREs might be mediated by DNA-binding proteins (indicated by X). (B) Transcription factors (TF), which act as co-activators for the transcription of _target genes, might block the recruitment of PcG protein complexes at non-PcG binding sites.
Figure 4
Figure 4. Polycomb-independent transcriptional activation by EZH2
(A) In ER-negative breast cancer cells, EZH2 activates NFκB _target genes through the formation of a ternary complex with the NFκB components, RelA and RelB, via a process that does not require other PRC2 subunits. (B) In ER-positive breast cancer cells, EZH2 physically interacts directly with ER-α and Wnt signaling components, activating their downstream _targets, like c-myc and cyclin D1, via RNA polymerase II transcription. (C) In castration-resistant prostate cancer (CRPC), phosphorylation of EZH2 at Ser21, mediated by the PI3K-Akt pathway, alters its function from a polycomb repressor to a transcriptional co-activator of the AR.
Figure 5
Figure 5. Non-polycomb functions of BMI1
(A) The PRC1 subunit, BMI1, acts as an activator of the WNT pathway by repressing the Dickkopf (DKK) family of WNT inhibitors. The Wnt/β-Catenin pathway regulates stem cell pluripotency and cell fate decisions during development. In the presence of the Wnt ligand, the co-receptor LRP5/6 forms a complex with Wnt-bound frizzled, activating disheveled (Dvl) by sequential phosphorylation, poly-ubiquitination, and polymerization, which displaces GSK-3β from APC/axin, causing the nuclear translocation of β-catenin and the subsequent recruitment of TCF DNA-binding factors as co-activators for transcription. BMI1 represses the expression of the DKK proteins. DKK1 repression leads to the upregulation of the WNT _target, c-Myc, which leads to further transcriptional autoactivation of BMI1. (B) The binding of TNFα to the TNF receptor (TNFR), causes the recruitment of TNFR1-associated death domain protein (TRADD), receptor-interacting protein (RIP) and TNF receptor-associated factor 2 (TRAF2) to the cell membrane. Then, the IκB kinase (IKK) complex, composed of IKKα, IKKβ, and IKKγ/NFkB essential modulator (NEMO), is recruited to the TNFR1 signaling complex, which leads to IKKβ phosphorylation and activation. This results in the nuclear translocation of NFκB and its subsequent transactivation. BMI1 stimulates IKKβ phosphorylation and the nuclear translocation of NFκB, which stimulates Myc. This, in turn, activates BMI1, leading to a positive feedback loop.
Figures 6
Figures 6. Role of RYBP in apoptosis and the PcG-MDM2-p53 pathway
RYBP enhances Fas-induced apoptosis. When the Fas receptor is bound by a ligand, the adaptor molecule Fas-associated protein with death domain (FADD), interacts with procaspase-8 and procaspase-10 to form the death-inducing signaling complex (DISC). RYBP interacts with FADD and caspases-8 and -10, enhancing the formation of the DISC and promoting Fas-mediated apoptosis. RYBP also binds to HIPPI and promotes neuronal apoptosis. RYBP forms a ternary complex with p53 and MDM2, preventing p53 ubiquitination and degradation. On the other hand, ring finger protein 2 (RNF2), an E3 ubiquitin ligase, promotes p53 ubiquitination but stabilizes MDM2, inhibiting its autoubiquitination.
Figure 7
Figure 7. Schematic representation of the aberrant polycomb signaling in cancer
The functions of many proteins from polycomb complexes are altered by aberrant expression, missense mutations, or chromosomal translocations in human cancers, likely leading to changes in transcriptional programs and cell states. The overexpression or aberrant expression of polycomb proteins leads to uncontrolled cell growth, invasion, resistance to cell death, and defective stem cell renewal patterns. During development, polycomb proteins mediate appropriate body planning and differentiation (A: anterior; P: posterior), which is disrupted in cancerous cells and defective stem cells. Non-coding RNAs (ncRNA) mediate polycomb gene silencing by helping recruit PcG protein complexes. In cancer cells, tumor suppressor miRNAs are downregulated. These miRNAs typically _target the oncogenic polycomb proteins, leading to their degradation.
Figure 8
Figure 8. PcG proteins and miRNAs
(A) The expression of Ezh2, SUZ12, and Bmi1 is regulated at the post-transcriptional level by miRNAs, _targeting their 3′UTR, and leading to transcript degradation. The miRNA complex is formed by TRBP (the human immunodeficiency virus transactivating response RNA-binding protein), argonaute 2 (Ago2), and dicer, which facilitates the recognition of PcG protein transcripts or marks them for cleavage. (B) Regulation of miRNA expression by polycomb proteins (e.g., the miR31-PRC2-NFκB axis). PRC2 overexpression leads to H3K27Me3 deposition on MiR-31 and its subsequent silencing. This leads to the overexpression of NIK and activation of NFκB-mediated survival and inflammatory pathways.
Figure 9
Figure 9. _targeting PcG proteins for cancer therapy
Aberrant gene silencing in cancer involves transcriptional repressive complexes (such as PRC1/PRC2) in the gene promoter region, and interactions between DNA methylation machinery and chromatin modifiers (such as histone deacetylase, HDAC). Pharmacological inhibition of individual components of the transcriptionally repressive chromatin with DNMT inhibitors, HDAC inhibitors, or PRC inhibitors that inhibit the H3K27Me mark either alone or in combination, may result in DNA demethylation and complex disintegration, leading to the reactivation of critical tumor suppressor genes, including those associated with lineage commitment, immunomodulation, major cell signaling pathways, programmed cell death, and other processes. HAT: histone acetylase. Pol II: RNA polymerase II.
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