1,615 publications from this institution
Gene transcription can be activated or inhibited by a reversible modification of the gene; this modification is termed an epigenetic change. This account of epigenetics in cancer reviews the mechanisms and consequences of epigenetic changes in cancer cells and concludes with the implications of these changes for the diagnosis, prognosis, and treatment of cancer.
Sotos syndrome is an autosomal dominant condition characterized by overgrowth resulting in tall stature and macrocephaly, together with an increased risk of tumorigenesis. The disease is caused by loss-of-function mutations and deletions of the nuclear receptor SET domain containing protein-1 (NSD1) gene, which encodes a histone methyltransferase involved in chromatin regulation. However, despite its causal role in Sotos syndrome and the typical accelerated growth of these patients, little is known about the putative contribution of NSD1 to human sporadic malignancies. Here, we report that NSD1 function is abrogated in human neuroblastoma and glioma cells by transcriptional silencing associated with CpG island-promoter hypermethylation. We also demonstrate that the epigenetic inactivation of NSD1 in transformed cells leads to the specifically diminished methylation of the histone lysine residues H4-K20 and H3-K36. The described phenotype is also observed in Sotos syndrome patients with NSD1 genetic disruption. Expression microarray data from NSD1-depleted cells, followed by ChIP analysis, revealed that the oncogene MEIS1 is one of the main NSD1 targets in neuroblastoma. Furthermore, we show that the restoration of NSD1 expression induces tumor suppressor-like features, such as reduced colony formation density and inhibition of cellular growth. Screening a large collection of different tumor types revealed that NSD1 CpG island hypermethylation was a common event in neuroblastomas and gliomas. Most importantly, NSD1 hypermethylation was a predictor of poor outcome in high-risk neuroblastoma. These findings highlight the importance of NSD1 epigenetic inactivation in neuroblastoma and glioma that leads to a disrupted histone methylation landscape and might have a translational value as a prognostic marker.
Abstract Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators, as well as by a number of reversible modifications of DNA and histones that are commonly referred to as epigenetic marks. Such alterations (i.e., methylation, acetylation, and ubiquitination) are catalyzed by an array of dedicated enzymes with antagonistic activity, including methyltransferases and demethylases, acetyltransferases and deacetylases, as well as ubiquitin ligases and deubiquitinating enzymes. The epigenetic control of transcription is critical not only for embryonic and postembryonic development but also for the preservation of homeostasis in all adult tissues. In line with this notion, epigenetic defects have been associated with a variety of human disorders, including (but not limited to) congenital conditions as well as multiple hematological and solid tumors. Here, we provide an in-depth discussion of the impact of epigenetic alterations on cancer stemness, i.e., the ability of a small population of poorly differentiated malignant cells to (1) self-renew while generating a more differentiated progeny, and (2) exhibit superior tumor initiating/repopulating potential along with exceptional plasticity and improved resistance to environmental and therapy-elicited stress. Moreover, we critically evaluate the potential and limitations of targeting epigenetic modifiers as a means to eradicate cancer stem cells for therapeutic purposes.
Epigenetic processes, defined as the heritable patterns of gene expression that do not involve changes in the sequence of the genome, and their effects on gene repression are increasingly understood to be such a way of modulating phenotype transmission and development. The patterns of DNA methylation, histone modifications, microRNAs, and several chromatin-related proteins of sick cells usually differ from those of healthy cells, highlighting the importance of epigenetic regulation in most human pathologies. This chapter provides an overview of how epigenetic factors contribute to the development of human diseases, such as abnormal imprinting-causative pathologies, cancer malignancies, as well as autoimmune, cardiovascular, and neurological disorders. These studies have provided extensive information about the mechanisms that contribute to the phenotype of human diseases, but also provided opportunities for therapy.
Changes in chromatin structure are an essential mechanism for gene regulation (transcription, replication, DNA repair and recombination). ATP-dependent chromatin-remodeling enzymes have previously been implicated in maintaining and regulating chromatin structure. These enzymes are divided into several groups including the SWI/SNF, ISWI and CHD families. Although the Chromodomain Helicase DNA-binding protein (CHD) family members are involved in key cellular processes, the disrupted regulation of their expression has not been fully assessed. An impairment of chromatin remodeling activity, mediated by promoter CpG island hypermethylation of the described candidate genes, could be key in cancer pathology. Herein, we examine the DNA methylation profiles of CHD family members (CHD1-9) in different tumor types. For all CHDs, CpG island hypermethylation was only observed at the CHD5 promoter in human cancer cell lines and primary tumors, particularly gliomas and colon and breast carcinomas. RT-qPCR analyses correlated CHD5 loss of expression with hypermethylation of the promoter, and restoration of CHD5 mRNA levels upon treatment with a DNA demethylating agent. These results underpin the epigenetic inactivation of the chromating remodeling factor CHD5 as one contributor for the aberrant structural changes of chromatin throughout the genome of the cancer cell.
