Context-dependent actions of Polycomb repressors in cancer

Koppens, Martijn A.J.; Lohuizen, Maarten van

doi:10.1038/onc.2015.195

Cited by 88 publications

(82 citation statements)

References 196 publications

(184 reference statements)

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“…3A). The literature linking PcG and TrxG proteins to cancer, however, is vast and complicated with perhaps more questions raised than answered (see reviews by Grossniklaus and Paro, 2014;Kingston and Tamkun, 2014;Koppens and van Lohuizen, 2015;Sauvageau and Sauvageau, 2010;Scelfo et al, 2015). Indeed, lending support to many PcG proteins serving as oncogenes, overexpression of the genes encoding PcG proteins is widespread in a multitude of cancer types (Grossniklaus and Paro, 2014;Koppens and van Lohuizen, 2015).…”

Section: Trxg and Pcg Activities Out Of Balance In Diseasementioning

confidence: 99%

“…Nonetheless, the exact same factors in many instances have been implicated as tumor suppressors in a different context. EZH2 provides a compelling example of this, in which activating mutations result in lymphomas and overexpression is seen in a number of solid tumors yet inactivating mutations promote myeloid malignancies (Hock, 2012;Koppens and van Lohuizen, 2015). Perhaps context-dependent considerations, such as the exact cohort of misregulated targets within the cell and the balance between PcG and TrxG regulation, influence whether these chromatin regulators function as tumor suppressors versus oncogenes (Koppens and van Lohuizen, 2015).…”

Section: Trxg and Pcg Activities Out Of Balance In Diseasementioning

confidence: 99%

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Trithorax and Polycomb group-dependent regulation: a tale of opposing activities

2015

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Intricate layers of regulation determine the unique gene expression profiles of a given cell and, therefore, underlie the immense phenotypic diversity observed among cell types. Understanding the mechanisms that govern which genes are expressed and which genes are silenced is a fundamental focus in biology. The Polycomb and Trithorax group chromatin proteins play important roles promoting the stable and heritable repression and activation of gene expression, respectively. These proteins, which are conserved across metazoans, modulate post-translational modifications on histone tails and regulate nucleosomal structures. Here, we review recent advances that have shed light on the mechanisms by which these two classes of proteins act to maintain epigenetic memory and allow dynamic switches in gene expression during development.

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Section: Trxg and Pcg Activities Out Of Balance In Diseasementioning

confidence: 99%

Section: Trxg and Pcg Activities Out Of Balance In Diseasementioning

confidence: 99%

Trithorax and Polycomb group-dependent regulation: a tale of opposing activities

2015

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“…RNA extraction, reverse-transcription, fractionation and qPCR were performed as described in ref. 38. The Applied Biosystems TaqMan probes Hs00978815_m1, Hs03298696_s1, Hs02800695_m1, and Hs02758991_g1 were used for MIAT, snoRNA55, HPRT1 and GAPDH, respectively.…”

Section: Supplementary Materialsmentioning

confidence: 99%

“…The two main PRCs (PRC1 and PRC2) act in concert to silence gene transcription. PRC2 functions to trimethylate histone H3 lysine 27 (H3K27me3) in the promoter region of a target gene, thus creating a repressive chromatin mark [38]. This histone modification is subsequently recognized by the chromodomain of the CBX polycomb proteins (CBX2,4,6,7,8) [39] which facilitate the recruitment of the PRC1 to the chromatin [40].…”

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confidence: 99%

The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer

et al. 2016

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Neuroendocrine prostate cancer (NEPC) is the most lethal prostatic neoplasm.NEPC is thought to originate from the trans-differentiation of AR-positive adenocarcinoma cells. We have previously shown that an epigenetic/non-coding interactome (ENI) orchestrates cancer cells' plasticity, thereby allowing the emergence of metastatic, drugresistant neoplasms. The primary objective of this manuscript is to discuss evidence indicating that some components of the ENI (Polycomb genes, microRNAs) play a key role in NEPC initiation and progression. Long non-coding RNAs (lncRNAs) represent vast and largely unexplored component of the ENI. Their role in NEPC has not been investigated. We show preliminary evidence indicating that a lncRNA (MIAT) is selectively up-regulated in NEPCs and might interact with Polycomb genes. Our results indicate that lncRNAs can be exploited as new biomarkers and therapeutic targets for NEPC.Keywords: Neuroendocrine prostate cancer; MIAT; Long non-coding RNAs; Polycomb; Epigenetic/non-coding interactome; Trans-differentiation. Neuroendocrine Prostate Cancer: Clinical and Molecular FeaturesIn adult males, the prostate is a small acorn-shaped tissue with ductal-acinar histology surrounding the urethra at the base of the bladder. Its main function is to contribute secretory proteins to the seminal fluid [1]. The adult prostate is a pseudo-stratified epithelium composed of three main cell lineages (Fig.1, left panel): 1) secretory luminal cells are the predominant cell type; these cells express keratins (K8, K18), the androgen receptor (AR) and secretory proteins such as prostate-specific antigen (PSA) and prostatic specific acid phosphatase (PSAP);2) basal cells expressing K5 and K14 keratins and p63 are the second major cell type;3) neuroendocrine cells (NEC) expressing chromogranin A (CHGA), synaptophysin (SYP), and neuropeptides are scattered throughout the basal layer and comprise less than 1% of normal prostatic glandular epithelium [1][2][3].Prostate cancer (PCa) represents the second most frequently diagnosed neoplasm and is the sixth leading cause of cancer-related deaths in males worldwide [4,5]. In keeping with the composition of prostate epithelium, more than 95% of PCas are classified as adenocarcinomas, which show luminal phenotype and AR expression [6] (Fig.1, middle panel).Endogenous androgens, mainly produced by the testis, bind to the AR and fuel prostate adenocarcinoma proliferation [7]. For this reason, androgen-deprivation therapy (a.k.a. castration) is an effective therapeutic strategy for this disease. However, patients invariably relapse despite castrate androgen levels (castration-resistant PCa, CRPC) mainly via genetic and epigenetic alterations that facilitate ligand-independent AR activation, amplify the ARdependent signaling, or trigger different proliferative pathways [7]. CRPCs are characterized by substantially worse prognoses, but chemotherapeutics and newly approved hormonal treatments (e.g., Enzalutamide [8] and Abiraterone [9]) are still effective in p...

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“…Emerging evidence suggests that PcG proteins could also be tumor suppressors (Grossniklaus and Paro, 2014;Koppens and van Lohuizen, 2015;Su et al, 2011). For example, loss of functional mutation of PRC2 rather than overexpression has been implicated in malignant myeloid diseases.…”

Section: Tumor Suppressive Function Of Pcg Genesmentioning

confidence: 99%

Control of germline stem cell differentiation by Polycomb and Trithorax group genes in the niche microenvironment

Chen

et al. 2016

Development

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Polycomb and Trithorax group (PcG and TrxG) genes function to regulate gene transcription by maintaining a repressive or active chromatin state, respectively. This antagonistic activity is important for body patterning during embryonic development, but whether this function module has a role in adult tissues is unclear. Here, we report that in the Drosophila ovary, disruption of the Polycomb repressive complex 1 (PRC1), specifically in the supporting escort cells, causes blockage of cystoblast differentiation and germline stem celllike tumor formation. Tumors are caused by derepression of decapentaplegic (dpp), which prevents cystoblast differentiation. Interestingly, activation of dpp in escort cells requires the function of the TrxG gene brahma (brm), suggesting that loss of PRC1 in escort cells causes Brm-dependent dpp expression. Our study suggests a requirement for balanced activity between PcG and TrxG in an adult stem cell niche, and disruption of this balance could lead to the loss of tissue homeostasis and tumorigenesis.

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Context-dependent actions of Polycomb repressors in cancer

Cited by 88 publications

References 196 publications

Trithorax and Polycomb group-dependent regulation: a tale of opposing activities

Trithorax and Polycomb group-dependent regulation: a tale of opposing activities

The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer

Control of germline stem cell differentiation by Polycomb and Trithorax group genes in the niche microenvironment

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