Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

Yamamoto, Yukiya; Abe, Akihiro; Emi, Nobuhiko

doi:10.1158/1541-7786.mcr-13-0596

Cited by 45 publications

(37 citation statements)

References 29 publications

(41 reference statements)

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“…On the other hand, BCOR and BCORL1 are part of a complex similar to the PRC1. 44 Cohesin is a multimeric protein complex that is conserved across species and is composed of 4 core subunits (SMC1A, SMC3, RAD21, and STAG proteins) together with a number of regulatory proteins such as NIPBL, PDS5, or ESCO proteins. 34 The 4 subunits form a ring structure that regulates chromosome segregation during meiosis and mitosis, but recent data suggest additional functions such as double-stranded DNA repair and regulation of transcription.…”

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confidence: 99%

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Duployez

Marceau-Renaut

Boissel

et al. 2016

Blood

191

186

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Key Points• Recurrent mutations in chromatin modifiers and cohesin were observed in t(8;21) AML, but not inv (16 . Mutations in genes activating tyrosine kinase signaling (including KIT, N/KRAS, and FLT3) were frequent in both subtypes of CBF-AML. In contrast, mutations in genes that regulate chromatin conformation or encode members of the cohesin complex were observed with high frequencies in t(8;21) AML (42% and 18%, respectively), whereas they were nearly absent in inv(16) AML. High KIT mutant allele ratios defined a group of t(8;21) AML patients with poor prognosis, whereas high N/KRAS mutant allele ratios were associated with the lack of KIT or FLT3 mutations and a favorable outcome. In addition, mutations in epigenetic modifying or cohesin genes were associated with a poor prognosis in patients with tyrosine kinase pathway mutations, suggesting synergic cooperation between these events. These data suggest that diverse cooperating mutations may influence CBF-AML pathophysiology as well as clinical behavior and point to potential unique pathogenesis of t(8;21) vs inv(16) AML.

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confidence: 99%

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Duployez

Marceau-Renaut

Boissel

et al. 2016

Blood

191

186

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“…The other member of the heterodimer is one out of a group of six Polycomb Ring finger proteins (whose best-known member is perhaps BMI1), thought to act as a positive cofactor (10,11). It has been shown that RING1B is involved in several human cancers (12)(13)(14)(15), especially in human hepatocellular carcinomas and pancreatic cancer (16). However, its exact function during the development of such cancers is yet unknown.…”

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confidence: 99%

Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

Santofimia‐Castaño

Rizzuti

Pey

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Intrinsically disordered proteins (IDPs) are ubiquitous in eukaryotes, and they are often associated with diseases in humans. The protein NUPR1 is a multifunctional IDP involved in chromatin remodeling and in the development and progression of pancreatic cancer; however, the details of such functions are unknown. Polycomb proteins are involved in specific transcriptional cascades and gene silencing. One of the proteins of the Polycomb complex is the Ring finger protein 1 (RING1). RING1 is related to aggressive tumor features in multiple cancer types. In this work we characterized the interaction between NUPR1 and the paralogue RING1B in vitro, in silico, and in cellulo. The interaction occurred through the C-terminal region of RING1B (C-RING1B), with an affinity in the low micromolar range (∼10 μM). The binding region of NUPR1, mapped by NMR, was a hydrophobic polypeptide patch at the 30s region of its sequence, as pinpointed by computational results and site-directed mutagenesis at Ala33. The association between C-RING1B and wild-type NUPR1 also occurred in cellulo as tested by protein ligation assays; this interaction is inhibited by trifluoperazine, a drug known to hamper binding of wild-type NUPR1 with other proteins. Furthermore, the Thr68Gln and Ala33Gln/Thr68Gln mutants had a reduction in the binding toward C-RING1B as shown by in vitro, in silico, and in cellulo studies. This is an example of a well-folded partner of NUPR1, because its other interacting proteins are also unfolded. We hypothesize that NUPR1 plays an active role in chromatin remodeling and carcinogenesis, together with Polycomb proteins.G ene expression control occurs through the combined activities of transcription factors and chromatin regulators, considered as effectors of epigenetic mechanisms. Posttranslational modifications of nucleosomal histones, DNA methylation, local compaction, and long-range interactions determine a variety of chromatin structures that can affect the transcriptional output.A group of chromatin regulators are the Polycomb Repressive complexes (PRCs) (1, 2). These Polycomb group (PcG) proteins are encoded by genes initially discovered over 60 years ago as repressors of the Hox genes in Drosophila (3). The PcG proteins form two main silencing heteromeric complexes called PRC1 and PRC2; both are highly conserved in eukaryotes and either in isolation or synergistically can silence genes (4, 5). The catalytic functions of both complexes include ubiquitin-ligase (H3K119ub1) and methyltransferase activity (H3K27Me3), respectively. In mammals, the PRC2 core is formed by, at least, four heteromeric units, one of which is EZH2 (or its paralog, EZH1), the methyltransferase that catalyzes the trimethylation of histone H3 at Lys27 (5). This modification can act as an anchoring site of PRC1 complexes containing chromobox (CBX) proteins. These CBX proteins recruit PRC1 complex onto PRC2-enriched chromatin, facilitating the monoubiquitylation. The PRC1-dependent monoubiquitylation at Lys119 of histone H2A correlates with transc...

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“…A major cause of cancer is through the dysregulation of proper transcriptional control, a process that is directly regulated by transcription factors, co-activators and co-repressors (24). Accumulating evidence indicates that the PC family of epigenetic proteins comprises transcriptional repressors that are often misregulated in various types of human cancer, and the expression level is associated with cancer progression (25), indicating that PcG proteins may exhibit oncogenic functions.…”

Section: Discussionmentioning

confidence: 99%

Rnf2 knockdown reduces cell viability and promotes cell cycle arrest in gastric cancer cells

et al. 2017

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Abstract. Rnf2 is a fundamental component of the polycomb repressive complex 1and acts as the really interesting new gene finger E3 ligase, which is responsible for histone 2A modification. Previous studies have shown that the ring finger protein 2 (Rnf2) is overexpressed in various types of tumor and has a close association with tumor development. However, few studies have been carried out into the expression and biological function of Rnf2 in gastric cancer cells. The present study measured the expression of Rnf2 in gastric cancer cells and normal epithelial gastric cells. The results demonstrate that Rnf2 is upregulated in gastric cancer cells. In addition, the knockdown of Rnf2 inhibited the cell viability and induced increased G1 phase followed by a substantial reduction of the G2/M phase. The expression levels of p21 and p27 were also significantly elevated by the knockdown of Rnf2. These results provide evidence of the oncogenic function of Rnf2 in gastric cancer, possibly through an inhibition of cellular proliferation and a delay of the G2/M phase. Therefore, Rnf2 may be a novel target for the prognosis and therapy of gastric cancer. IntroductionPolycomb group (PcG) proteins are epigenetic regulators for gene silencing at the transcription level, acting as important regulators of DNA repair, proliferation, embryonic differentiation and cell-fate maintenance during development and in adult tissue homeostasis (1-3). These proteins exist in at least two biochemically and functionally distinct PcG core complexes referred to as polycomb repressive complex (PRC) 1 and 2. PRC2, which is involved in the initiation of gene repression, mediates the trimethylation of histone H3 at Lys27 (H3K27me3) and consists of histone methyltransferase enhancer of zeste homolog 2 (EZH2), the polycomb repressive complex and embryonic ectoderm development (4,5). The mammalian PRC1, which is an ubiquitin E3 ligase complex, consists of polycomb (PC), polyhomeotic (PH), BMI1, ring finger protein (Rnf) 1A and 2 (Rnf2) (6), among which Rnf2 has been identified as the catalytic subunit (7). Rnf2, acts as the RING finger E3 ligase responsible for H2A modification in the PRC1 complex and influences early development and embryonic stem cell maintenance as well as cancer development (8,9). Recent evidence showed that Rnf2 is highly expressed in various types of tumor in comparison to normal tissue counterparts (10). Knockdown of Rnf2 in HeLa cells resulted in morphological changes and an inhibition of cellularproliferation (7), suggesting an oncogenic function of Rnf2. Additionally, it has been reported that Rnf2 can either directly or indirectly target a distinct, specific pathway involved in cell cycle control (11,12). However, in order to acquire a complete understanding of the mechanisms through which cancer progression is regulated by Rnf2, additional investigation is required.Normal cell cycle progression is tightly controlled by a variety of molecular checkpoints, which supervise the biological processes that take place in different...

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Clarifying the Impact of Polycomb Complex Component Disruption in Human Cancers

Cited by 45 publications

References 29 publications

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Comprehensive mutational profiling of core binding factor acute myeloid leukemia

Intrinsically disordered chromatin protein NUPR1 binds to the C-terminal region of Polycomb RING1B

Rnf2 knockdown reduces cell viability and promotes cell cycle arrest in gastric cancer cells

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