mSWI/SNF promotes Polycomb repression both directly and through genome-wide redistribution.

The mammalian SWI/SNF complex, or BAF complex, has a conserved and direct role in antagonizing Polycomb-mediated repression. Yet, BAF also promotes repression by Polycomb in stem cells and cancer. How BAF both antagonizes and promotes Polycomb-mediated repression remains unknown. Here, we utilize targeted protein degradation to dissect the BAF-Polycomb axis in mouse embryonic stem cells on short timescales. We report that rapid BAF depletion redistributes Polycomb repressive complexes PRC1 and PRC2 from highly occupied domains, like Hox clusters, to weakly occupied sites normally opposed by BAF. Polycomb redistribution from highly repressed domains results in their decompaction, gain of active epigenomic features and transcriptional derepression. Surprisingly, through dose-dependent degradation of PRC1 and PRC2, we identify a conventional role for BAF in Polycomb-mediated repression, in addition to global Polycomb redistribution. These findings provide new mechanistic insight into the highly dynamic state of the Polycomb-Trithorax axis.

Dynamic methylation of histone H3K18 in differentiating Theileria parasites.

Lysine methylation on histone tails impacts genome regulation and cell fate determination in many developmental processes. Apicomplexa intracellular parasites cause major diseases and they have developed complex life cycles with fine-tuned differentiation events. Yet, apicomplexa genomes have few transcription factors and little is known about their epigenetic control systems. Tick-borne Theileria apicomplexa species have relatively small, compact genomes and a remarkable ability to transform leucocytes in their bovine hosts. Here we report enriched H3 lysine 18 monomethylation (H3K18me1) on the gene bodies of repressed genes in Theileria macroschizonts. Differentiation to merozoites (merogony) leads to decreased H3K18me1 in parasite nuclei. Pharmacological manipulation of H3K18 acetylation or methylation impacted parasite differentiation and expression of stage-specific genes. Finally, we identify a parasite SET-domain methyltransferase (TaSETup1) that can methylate H3K18 and represses gene expression. Thus, H3K18me1 emerges as an important epigenetic mark which controls gene expression and stage differentiation in Theileria parasites.

EZH2: a novel target for cancer treatment.

Enhancer of zeste homolog 2 (EZH2) is enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2) that can alter downstream target genes expression by trimethylation of Lys-27 in histone 3 (H3K27me3). EZH2 could also regulate gene expression in ways besides H3K27me3. Functions of EZH2 in cells proliferation, apoptosis, and senescence have been identified. Its important roles in the pathophysiology of cancer are now widely concerned. Therefore, targeting EZH2 for cancer therapy is a hot research topic now and different types of EZH2 inhibitors have been developed. In this review, we summarize the structure and action modes of EZH2, focusing on up-to-date findings regarding the role of EZH2 in cancer initiation, progression, metastasis, metabolism, drug resistance, and immunity regulation. Furtherly, we highlight the advance of targeting EZH2 therapies in experiments and clinical studies.

Repression of microRNA-21 inhibits retinal vascular endothelial cell growth and angiogenesis via PTEN dependent-PI3K/Akt/VEGF signaling pathway in diabetic retinopathy.

Diabetic retinopathy (DR) is a microvascular complication of diabetes and one of the most common causes of blindness in active stage. This study is performed to explore the effects of microRNA-21 (miR-21) on retinal vascular endothelial cell (RVEC) viability and angiogenesis in rats with DR via the phosphatidylinositiol 3-kinase/protein kinase B (PI3K/Akt)/vascular endothelial growth factor (VEGF) signaling pathway by binding to phosphatase and tensin homolog (PTEN). Sprague Dawley (SD) rats were used for establishment of DR models. Target relationship between miR-21 and PTEN was assessed by bioinformatics prediction in combination with dual-luciferase reporter gene assay. Identification of expression of miR-21, PTEN and PI3K/Akt/VEGF signaling pathway-related genes in the retinal tissues was then conducted. In order to assess the contributory role of miR-21 in DR, the RVECs were transfected with mimic or inhibitor of miR-21, or siRNA-PTEN, followed by the detection of expression of PTEN and PI3K/Akt/VEGF-related genes, as well as the measurement of cell viability, cell cycle and apoptosis. Increased expression of miR-21 and PI3K/Akt/VEGF related genes, along with a reduced expression of PTEN was observed in the retinal tissues of DR rats. PTEN was targeted and negatively regulated by miR-21, while the PI3K/Akt/VEGF signaling pathway was activated by miR-21. RVECs transfected with miR-21 inhibitor exhibited promoted viability and angiogenesis, and inhibited apoptosis. To conclude, our results indicated that miR-21 overexpression could potentially stimulate RVEC viability and angiogenesis in rats with DR through activation of the PI3K/Akt/VEGF signaling pathway via repressing PTEN expression, highlighting the potential of miR-21 as a target for DR treatment.

DNA methylation dynamics at transposable elements in mammals.

Transposable elements dominate the mammalian genome, but their contribution to genetic and epigenetic regulation has been largely overlooked. This was in part due to technical limitations, which made the study of repetitive sequences at single copy resolution difficult. The advancement of next-generation sequencing assays in the last decade has greatly enhanced our understanding of transposable element function. In some instances, specific transposable elements are thought to have been co-opted into regulatory roles during both mouse and human development, while in disease such regulatory potential can contribute to malignancy. DNA methylation is arguably the best characterised regulator of transposable element activity. DNA methylation is associated with transposable element repression, and acts to limit their genotoxic potential. In specific developmental contexts, erasure of DNA methylation is associated with a burst of transposable element expression. Developmental regulation of DNA methylation enables transposon activation, ensuring their survival and propagation throughout the host genome, and also allows the host access to regulatory sequences encoded within the elements. Here I discuss DNA methylation at transposable elements, describing its function and dynamic regulation throughout murine and human development.

Class IIa HDACs regulate learning and memory through dynamic experience-dependent repression of transcription.

The formation of new memories requires transcription. However, the mechanisms that limit signaling of relevant gene programs in space and time for precision of information coding remain poorly understood. We found that, during learning, the cellular patterns of expression of early response genes (ERGs) are regulated by class IIa HDACs 4 and 5, transcriptional repressors that transiently enter neuronal nuclei from cytoplasm after sensory input. Mice lacking these repressors in the forebrain have abnormally broad experience-dependent expression of ERGs, altered synaptic architecture and function, elevated anxiety, and severely impaired memory. By acutely manipulating the nuclear activity of class IIa HDACs in behaving animals using a chemical-genetic technique, we further demonstrate that rapid induction of transcriptional programs is critical for memory acquisition but these programs may become dispensable when a stable memory is formed. These results provide new insights into the molecular basis of memory storage.

Contribution of DNMT1 to Neuropathic Pain Genesis Partially through Epigenetically Repressing Kcna2 in Primary Afferent Neurons.

Expressional changes of pain-associated genes in primary sensory neurons of DRG are critical for neuropathic pain genesis. DNA methyltransferase (DNMT)-triggered DNA methylation silences gene expression. We show here that DNMT1, a canonical maintenance methyltransferase, acts as the de novo DNMT and is required for neuropathic pain genesis likely through repressing at least DRG Kcna2 gene expression in male mice. Peripheral nerve injury upregulated DNMT1 expression in the injured DRG through the transcription factor cAMP response element binding protein-triggered transcriptional activation of Dnmt1 gene. Blocking this upregulation prevented nerve injury-induced DNA methylation within the promoter and 5'-untranslated region of Kcna2 gene, rescued Kcna2 expression and total Kv current, attenuated hyperexcitability in the injured DRG neurons, and alleviated nerve injury-induced pain hypersensitivities. Given that Kcna2 is a key player in neuropathic pain, our findings suggest that DRG DNMT1 may be a potential target for neuropathic pain management.SIGNIFICANCE STATEMENT In the present study, we reported that DNMT1, a canonical DNA maintenance methyltransferase, is upregulated via the activation of the transcription factor CREB in the injured DRG after peripheral nerve injury. This upregulation was responsible for nerve injury-induced de novo DNA methylation within the promoter and 5'-untranslated region of the Kcna2 gene, reductions in Kcna2 expression and Kv current and increases in neuronal excitability in the injured DRG. Since pharmacological inhibition or genetic knockdown of DRG DNMT1 alleviated nerve injury-induced pain hypersensitivities, DRG DNMT1 contributes to neuropathic pain genesis partially through repression of DRG Kcna2 gene expression.

Folate deficiency prevents neural crest fate by disturbing the epigenetic Sox2 repression on the dorsal neural tube.

Folate deficiency has been known to contribute to neural tube and neural crest defects, but why these tissues are particularly affected, and which are the molecular mechanisms involved in those abnormalities are important human health questions that remain unanswered. Here we study the function of two of the main folate transporters, FolR1 and Rfc1, which are robustly expressed in these tissues. Folate is the precursor of S-adenosylmethionine, which is the main donor for DNA, protein and RNA methylation. Our results show that knockdown of FolR1 and/or Rfc1 reduced the abundance of histone H3 lysine and DNA methylation, two epigenetic modifications that play an important role during neural and neural crest development. Additionally, by knocking down folate transporter or pharmacologically inhibiting folate transport and metabolism, we observed ectopic Sox2 expression at the expense of neural crest markers in the dorsal neural tube. This is correlated with neural crest associated defects, with particular impact on orofacial formation. By using bisulfite sequencing, we show that this phenotype is consequence of reduced DNA methylation on the Sox2 locus at the dorsal neural tube, which can be rescued by the addition of folinic acid. Taken together, our in vivo results reveal the importance of folate as a source of the methyl groups necessary for the establishment of the correct epigenetic marks during neural and neural crest fate-restriction.

A somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing.

Subsets of endogenous retroviruses (ERVs) are derepressed in mouse embryonic stem cells (mESCs) deficient for Setdb1, which catalyzes histone H3 lysine 9 trimethylation (H3K9me3). Most of those ERVs, including IAPs, remain silent if Setdb1 is deleted in differentiated embryonic cells; however they are derepressed when deficient for Dnmt1, suggesting that Setdb1 is dispensable for ERV silencing in somatic cells. However, H3K9me3 enrichment on ERVs is maintained in differentiated cells and is mostly diminished in mouse embryonic fibroblasts (MEFs) lacking Setdb1. Here we find that distinctive sets of ERVs are reactivated in different types of Setdb1-deficient somatic cells, including the VL30-class of ERVs in MEFs, whose derepression is dependent on cell-type-specific transcription factors (TFs). These data suggest a more general role for Setdb1 in ERV silencing, which provides an additional layer of epigenetic silencing through the H3K9me3 modification.

Gestación por sustitución: reflexiones desde la perspectiva pediátrica / No disponible

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The Emerging View of Aging as a Reversible Epigenetic Process.

The achievement of animal cloning and subsequent development of cell reprogramming technology are having a profound impact on our view of the mechanisms of aging in complex organisms. The experimental evidence showing that an adult somatic nucleus implanted into an enucleated oocyte can give rise to a whole new individual strongly suggests that the integrity of the genome of an adult nucleus is fully preserved. Here, we will review recent experimental evidence showing that pluripotency gene-based cell reprogramming can erase the epigenetic marks of aging and rejuvenate cells from old individuals reversing most signs of aging and that when induced pluripotent stem cells are differentiated back to the cell type of origin, the rejuvenated cells share many of the features of wild-type counterparts from young donors. This evidence supports the idea that progressive epigenetic dysregulation may be the key driver of organismal aging and challenges the conventional view of aging as an irreversible process. The model of aging as an epigenetic process provides an elegant explanation of a number of age-related processes difficult to explain by conventional theories of aging.

Promoter CpG-Site Methylation of the KAI1 Metastasis Suppressor Gene Contributes to Its Epigenetic Repression in Prostate Cancer.

BACKGROUND: Repression of the KAI1 metastasis suppressor gene is closely associated with malignancy and poor prognosis in many human cancer types including prostate cancer. Since gene repression in human cancers frequently results from epigenetic alterations by DNA methylation and histone modifications, we examined whether the KAI1 gene becomes silenced through these epigenetic mechanisms in prostate cancer. METHODS: KAI1 mRNA and protein levels were determined by RT-PCR and immunoblotting analyses, respectively. Methylation status of the KAI1 promoter DNA in prostate cancer cell lines and tissues was evaluated by methylation-specific PCR analysis of bisulfite-modified genomic DNAs. Methylated CpG sites in the KAI1 promoter were identified by sequencing the PCR clones of the bisulfite-modified KAI1 promoter DNA. KAI1 protein levels in human prostate cancer tissue samples were examined by immunofluorescence staining of the tissues with an anti-KAI1 antibody. RESULTS: Among the three human prostate cancer cell lines examined, PC3 and DU145 cells exhibited markedly decreased levels of KAI1 mRNA and protein as compared to LNCaP cells, even though the exogenous KAI1 promoter not being methylated was normally functional in all these cell lines. Treatment of the low KAI1-expressing cell lines with a demethylating agent, 5'-aza-2'-deoxycytidine, significantly elevated KAI1 expression levels, implicating the involvement of DNA methylation in KAI1 downregulation. Methylation of CpG islands within the KAI1 promoter region was observed in the low KAI1-expressing cells, but not in the high KAI1-expressing cells. Also, methyl CpG-binding proteins such as MBD2 and MeCP2 were complexed to the KAI1 promoter in the low KAI1-expressing cells. Bisulfite sequencing analysis identified the intensively methylated CpG residues in the KAI1 promoter clones derived from prostate cancer cells and tissues with no or low KAI1 expression. As in prostate cancer cell lines, prostate cancer tissues from patients also displayed a negative association between KAI1 expression levels and methylation status of the KAI1 promoter. CONCLUSIONS: The present data suggest that the KAI1 gene might be repressed by epigenetic alterations through the promoter CpG-site methylation during prostate cancer progression. This epigenetic mechanism could provide a clue for understanding how the KAI1 gene was silenced in metastatic prostate cancers. Prostate 77: 350-360, 2017. © 2016 Wiley Periodicals, Inc.

Mecanismos epigenéticos en el desarrollo de la memoria y su implicación en algunas enfermedades neurológicas / Epigenetic mechanisms in the development of memory and their involvement in certain neurological diseases

Introducción: Hoy en día se acepta que el sistema nervioso central adulto posee una enorme flexibilidad morfofuncional que le permite realizar procesos de remodelación estructural aún después de haber alcanzado su desarrollo y maduración. Además del enorme número de genes que participan en el desarrollo de la memoria, los diferentes mecanismos epigenéticos conocidos también han sido involucrados en procesos de modificación neuronal normal y patológica y, por ende, en los mecanismos de desarrollo de la memoria. Desarrollo: Este trabajo fue llevado a cabo a través de una sistemática revisión de las bases de datos de publicaciones biomédicas sobre los aspectos genéticos y epigenéticos que participan en la función sináptica y la memoria. Conclusiones: La activación de la expresión génica, en respuesta a estímulos extrínsecos, ocurre también en células nerviosas diferenciadas. La actividad neuronal induce formas específicas de plasticidad sináptica que permiten la formación y almacenamiento de la memoria a largo plazo. Los mecanismos epigenéticos tienen un papel crucial en los procesos de modificación sináptica y en la formación y desarrollo de la memoria. Alteraciones en estos mecanismos producen déficit cognitivo y de memoria en padecimientos neurodegenerativos (enfermedad de Alzheimer y Huntington) así como en trastornos del desarrollo neurológico (síndrome de Rett, X-frágil y esquizofrenia). Los resultados obtenidos en diferentes modelos muestran, sin embargo, un escenario promisorio con tratamientos potenciales para algunos de estos padecimientos

Introduction: Today, scientists accept that the central nervous system of an adult possesses considerable morphological and functional flexibility, allowing it to perform structural remodelling processes even after the individual is fully developed and mature. In addition to the vast number of genes participating in the development of memory, different known epigenetic mechanisms are involved in normal and pathological modifications to neurons and therefore also affect the mechanisms of memory development. Development: This study entailed a systematic review of biomedical article databases in search of genetic and epigenetic factors that participate in synaptic function and memory. Conclusions: The activation of gene expression in response to external stimuli also occurs in differentiated nerve cells. Neural activity induces specific forms of synaptic plasticity that permit the creation and storage of long-term memory. Epigenetic mechanisms play a key role in synaptic modification processes and in the creation and development of memory. Changes in these mechanisms result in the cognitive and memory impairment seen in neurodegenerative diseases (Alzheimer disease, Huntington disease) and in neurodevelopmental disorders (Rett syndrome, fragile X, and schizophrenia). Nevertheless, results obtained from different models are promising and point to potential treatments for some of these diseases

The hinge domain of the epigenetic repressor Smchd1 adopts an unconventional homodimeric configuration.

The structural maintenance of chromosomes (SMC) proteins are fundamental to chromosome organization. They share a characteristic domain structure, featuring a central SMC hinge domain that is critical for forming SMC dimers and interacting with nucleic acids. The structural maintenance of chromosomes flexible hinge domain containing 1 (Smchd1) is a non-canonical member of the SMC family. Although it has been well established that Smchd1 serves crucial roles in epigenetic silencing events implicated in development and disease, much less is known about the structure and function of the Smchd1 protein. Recently, we demonstrated that the C-terminal hinge domain of Smchd1 forms a nucleic acid-binding homodimer; however, it is unclear how the protomers are assembled within the hinge homodimer and how the full-length Smchd1 protein is organized with respect to the hinge region. In the present study, by employing SAXS we demonstrate that the hinge domain of Smchd1 probably adopts an unconventional homodimeric arrangement augmented by an intermolecular coiled coil formed between the two monomers. Such a dimeric structure differs markedly from that of archetypical SMC proteins, raising the possibility that Smchd1 binds chromatin in an unconventional manner.

Ezh2-mediated repression of a transcriptional pathway upstream of Mmp9 maintains integrity of the developing vasculature.

Maintenance of vascular integrity is required for embryogenesis and organ homeostasis. However, the gene expression programs that stabilize blood vessels are poorly understood. Here, we show that the histone methyltransferase Ezh2 maintains integrity of the developing vasculature by repressing a transcriptional program that activates expression of Mmp9. Inactivation of Ezh2 in developing mouse endothelium caused embryonic lethality with compromised vascular integrity and increased extracellular matrix degradation. Genome-wide approaches showed that Ezh2 targets Mmp9 and its activators Fosl1 and Klf5. In addition, we uncovered Creb3l1 as an Ezh2 target that directly activates Mmp9 gene expression in the endothelium. Furthermore, genetic inactivation of Mmp9 rescued vascular integrity defects in Ezh2-deficient embryos. Thus, epigenetic repression of Creb3l1, Fosl1, Klf5 and Mmp9 by Ezh2 in endothelial cells maintains the integrity of the developing vasculature, potentially linking this transcriptional network to diseases with compromised vascular integrity.

Association of reduced type IX collagen gene expression in human osteoarthritic chondrocytes with epigenetic silencing by DNA hypermethylation.

OBJECTIVE: To investigate whether the changes in collagen gene expression in osteoarthritic (OA) human chondrocytes are associated with changes in the DNA methylation status in the COL2A1 enhancer and COL9A1 promoter. METHODS: Expression levels were determined using quantitative reverse transcription-polymerase chain reaction, and the percentage of DNA methylation was quantified by pyrosequencing. The effect of CpG methylation on COL9A1 promoter activity was determined using a CpG-free vector; cotransfections with expression vectors encoding SOX9, hypoxia-inducible factor 1α (HIF-1α), and HIF-2α were carried out to analyze COL9A1 promoter activities in response to changes in the methylation status. Chromatin immunoprecipitation assays were carried out to validate SOX9 binding to the COL9A1 promoter and the influence of DNA methylation. RESULTS: Although COL2A1 messenger RNA (mRNA) levels in OA chondrocytes were 19-fold higher than those in the controls, all of the CpG sites in the COL2A1 enhancer were totally demethylated in both samples. The levels of COL9A1 mRNA in OA chondrocytes were 6,000-fold lower than those in controls; 6 CpG sites of the COL9A1 promoter were significantly hypermethylated in OA patients as compared with controls. Treatment with 5-azadeoxycitidine enhanced COL9A1 gene expression and prevented culture-induced hypermethylation. In vitro methylation decreased COL9A1 promoter activity. Mutations in the 5 CpG sites proximal to the transcription start site decreased COL9A1 promoter activity. Cotransfection with SOX9 enhanced COL9A1 promoter activity; CpG methylation attenuated SOX9 binding to the COL9A1 promoter. CONCLUSION: This first demonstration that hypermethylation is associated with down-regulation of COL9A1 expression in OA cartilage highlights the pivotal role of epigenetics in OA, involving not only hypomethylation, but also hypermethylation, with important therapeutic implications for OA treatment.

Large hypomethylated domains serve as strong repressive machinery for key developmental genes in vertebrates.

DNA methylation is a fundamental epigenetic modification in vertebrate genomes and a small fraction of genomic regions is hypomethylated. Previous studies have implicated hypomethylated regions in gene regulation, but their functions in vertebrate development remain elusive. To address this issue, we generated epigenomic profiles that include base-resolution DNA methylomes and histone modification maps from both pluripotent cells and mature organs of medaka fish and compared the profiles with those of human ES cells. We found that a subset of hypomethylated domains harbor H3K27me3 (K27HMDs) and their size positively correlates with the accumulation of H3K27me3. Large K27HMDs are conserved between medaka and human pluripotent cells and predominantly contain promoters of developmental transcription factor genes. These key genes were found to be under strong transcriptional repression, when compared with other developmental genes with smaller K27HMDs. Furthermore, human-specific K27HMDs show an enrichment of neuronal activity-related genes, which suggests a distinct regulation of these genes in medaka and human. In mature organs, some of the large HMDs become shortened by elevated DNA methylation and associate with sustained gene expression. This study highlights the significance of domain size in epigenetic gene regulation. We propose that large K27HMDs play a crucial role in pluripotent cells by strictly repressing key developmental genes, whereas their shortening consolidates long-term gene expression in adult differentiated cells.

Rescue of a primary myelofibrosis model by retinoid-antagonist therapy.

Molecular targeting of the two receptor interaction domains of the epigenetic repressor silencing mediator of retinoid and thyroid hormone receptors (SMRT(mRID)) produced a transplantable skeletal syndrome that reduced radial bone growth, increased numbers of bone-resorbing periosteal osteoclasts, and increased bone fracture risk. Furthermore, SMRT(mRID) mice develop spontaneous primary myelofibrosis, a chronic, usually idiopathic disorder characterized by progressive bone marrow fibrosis. Frequently linked to polycythemia vera and chronic myeloid leukemia, myelofibrosis displays high patient morbidity and mortality, and current treatment is mostly palliative. To decipher the etiology of this disease, we identified the thrombopoietin (Tpo) gene as a target of the SMRT-retinoic acid receptor signaling pathway in bone marrow stromal cells. Chronic induction of Tpo in SMRT(mRID) mice results in up-regulation of TGF-ß and PDGF in megakaryocytes, uncontrolled proliferation of bone marrow reticular cells, and fibrosis of the marrow compartment. Of therapeutic relevance, we show that this syndrome can be rescued by retinoid antagonists, demonstrating that the physical interface between SMRT and retinoic acid receptor can be a potential therapeutic target to block primary myelofibrosis disease progression.

[Three-dimensional genome organization: a lesson from the Polycomb-Group proteins]. / L'organisation tridimensionnelle du génome à partir des protéines du groupe Polycomb.

As more and more genomes are being explored and annotated, important features of three-dimensional (3D) genome organization are just being uncovered. In the light of what we know about Polycomb group (PcG) proteins, we will present the latest findings on this topic. The PcG proteins are well-conserved chromatin factors that repress transcription of numerous target genes. They bind the genome at specific sites, forming chromatin domains of associated histone modifications as well as higher-order chromatin structures. These 3D chromatin structures involve the interactions between PcG-bound regulatory regions at short- and long-range distances, and may significantly contribute to PcG function. Recent high throughput "Chromosome Conformation Capture" (3C) analyses have revealed many other higher order structures along the chromatin fiber, partitioning the genomes into well demarcated topological domains. This revealed an unprecedented link between linear epigenetic domains and chromosome architecture, which might be intimately connected to genome function.

Frequent epigenetic silencing of PCDH10 by methylation in human colorectal cancer.

PURPOSE: Aberrant DNA methylation is common in cancer cells. Epigenetic alterations resulting in the loss of tumor suppression gene functions are frequently involved in tumor development and progression. Recently, methylation of PCDH10 was reported to be associated with multiple hematologic malignancies as well as some solid tumors. Whether the down-regulation of PCDH10 happens in CRC remains unknown. METHODS: Methylation status of PCDH10 was evaluated by methylation-specific PCR analysis. The effects of PCDH10 re-expression were determined in growth, colony formation, cell cycle, and invasion assays. RESULTS: In this study, we found that 100 % (8 of 8) of colorectal cancer cell lines were silenced for PCDH10, but not normal colorectal epithelial cells. Demethylation treatment confirmed that the reduced expression is associated closely with promoter methylation. Hyper-methylation of PCDH10 was also detected in 85 % of primary colorectal tumors, but not in adjacent normal colorectal tissues. CONCLUSIONS: Our results suggest that PCDH10 is an important tumor suppression gene with key roles of suppressing cell proliferation, clonogenicity, and inhibiting cell invasion in the development of colorectal cancer. Thus, PCDH10 methylation may constitute a useful biomarker of colorectal cancer patients.