Cancer, Epigenetics And The Nobel Prizes

The Nobel Prize in Physiology or Medicine 2012 have been awarded jointly to Sir John B. Gurdon and Shinya Yamanaka “for the discovery that mature cells can be reprogrammed to become pluripotent” as it is described in the Nobel Prize web site. Professors Gurdon and Yamanaka have all the merits to be bestowed with such a prestigious award for their seminal discoveries in the area. However, we can also consider this annual prize as a recognition to Epigenetics, similarly to the Nobel Prize of 2006 for Andrew Z. Fire and Craig C. Mello for their of RNA interference - gene silencing by doublestranded RNA. Reprogramming requires changing the epigenome of the cells and non-coding RNAs are critical elements in the establishment of epigenetic pattern

Epigenetic changes in cancer

Interest in epigenetics is now booming in all the biomedical fields. Initially, interest was sparked within the field of cancer research with the finding of global DNA hypomethylation events in the 1980s, followed by the CpG island hypermethylation of tumor suppressor genes in the 1990s and the approval of DNA demethylating drugs and histone deactylase inhibitors in the 2000s. For transformed cells, the arena is also expanding to include the wide spectrum of histone modification changes and the interaction with noncoding RNAs. What lies ahead is even more exciting, with the imminent completion of many human cancer epigenomes that will form the basis of better biomarkers and epigenetic drugs

Epigenetics in Cancer

Classic genetics alone cannot explain the diversity of phenotypes within a population. Nor does classic genetics explain how, despite their identical DNA sequences, monozygotic twins or cloned animals can have different phenotypes and different susceptibilities to a disease. The concept of epigenetics offers a partial explanation of these phenomena. First introduced by C.H. Waddington in 1939 to name "the causal interactions between genes and their products, which bring the phenotype into being," epigenetics was later defined as heritable changes in gene expression that are not due to any alteration in the DNA sequence

Aberrant Epigenetic Landscape in Cancer: How Cellular Identity Goes Awry

Appropriate patterns of DNA methylation and histone modifications are required to assure cell identity, and their deregulation can contribute to human diseases, such as cancer. Our aim here is to provide an overview of how epigenetic factors, including genomic DNA methylation, histone modifications, and microRNA regulation, contribute to normal development, paying special attention to their role in regulating tissue-specific genes. In addition, we summarize how these epigenetic patterns go awry during human cancer development. The possibility of “resetting” the abnormal cancer epigenome by applying pharmacological or genetic strategies is also discussed

DNA methylation in stem cell renewal and multipotency

Owing to their potential for differentiation into multiple cell types, multipotent stem cells extracted from many adult tissues are an attractive stem cell resource for the replacement of damaged tissues in regenerative medicine. The requirements for cellular differentiation of an adult stem cell are a loss of proliferation potential and a gain of cell-type identity. These processes could be restricted by epigenetic modifications that prevent the risks of lineage-unrelated gene expression or the undifferentiated features of stem cells in adult somatic cells. In this review, we focus on the role of DNA methylation in controlling the transcriptional activity of genes important for self-renewal, the dynamism of CpG methylation of tissue-specific genes during several differentiation programs, and whether the multilineage potential of adult stem cells could be imposed early in the original precursor stem cells through CpG methylation. Additionally, we draw attention to the role of DNA methylation in adult stem cell differentiation by reviewing the reports on spontaneous differentiation after treatment with demethylating agents and by considering the evidence provided by reprogramming of somatic cells into undifferentiated cells (that is, somatic nuclear transfer or generation of induced pluripotent cells). It is clear from the evidence that DNA methylation is necessary for controlling stem cell proliferation and differentiation, but their exact contribution in each lineage program is still unclear. As a consequence, in a clinical setting, caution should be exerted before employing adult stem cells or their derivatives in regenerative medicine and appropriate tests should be applied to ensure the integrity of the genome and epigenome

Towards a 'druggable' epitranscriptome: Compounds that target RNA modifications in cancer

Epitranscriptomics is an exciting emerging area that studies biochemical modifications of RNA. The field is boosted by the technical efforts of the last decade to characterize and quantify RNA modifications which have led to a map of post-transcripcional RNA marks in normal cell fate and develoment. However, the scientific interest has been fueled by the discovery of aberrant epitranscriptomes associated with human diseases, mainly cancer. The challenge is now to see whether epitrancriptomics offers a tunable mechanims to be targeted by small- molecule intervention. In this review, we will describe the principal RNA modifications (with a focus on mRNA), summarize the latest scientific evidences of their dysregulation in cancer and provide an overview of the state-of-the-art drug discovery to target the epitranscriptome. Finally, we will discuss the principal challenges in the field of chemical biology and drug development to increase the potential of targeted-RNA for clinical benefit

Extraordinary cancer epigenomics: thinking outside the classical coding and promoter box

The advent of functional genomics powered by high-throughput sequencing has given us a new appreciation of the genomic sequences that lie outside the canonical promoter-coding sequence box. These regions harbor distant regulatory elements, enhancers, super-enhancers, insulators, alternative promoters, and sequences that transcribe as noncoding RNAs (ncRNAs) such as miRNAs and long ncRNAs. These functional genomics studies have also enabled a clearer understanding of the role of the 3D structure of the genome in epigenetic regulation. Here we review the impact that epigenetic changes, and specifically DNA methylation, have on these extraordinary sequences in driving cancer progression

Insights from the genetic and transcriptional characterization of a cancer of unknown primary (CUP)

Cancer of unknown primary (CUP) defines a heterogeneous group of metastatic tumors that lack an identifiable primary tumor, despite a standardized diagnostic work-up (Fizazi et al, 2015). CUPs are characterized by an aggressive clinical course, unusual metastatic pattern, and poor prognosis. Research in this field has been encouraged to unravel the complexity of this enigmatic entity and improve clinical management and survival of CUP patients. In this issue of EMBO Molecular Medicine, Benvenuti et al (2020) describe the molecular characterization of multiple synchronous and spatially distinct metastases from a CUP patient, shedding light on the evolutionary dynamic and distinctive features of CUP

Hot topics in epigenetic mechanisms of aging: 2011

Aging is a complex process that results in compromised biological functions of the organism and increased susceptibility to disease and death. Although the molecular basis of aging is currently being investigated in many experimental contexts, there is no consensus theory to fully explain the aging process. Epigenetic factors, including DNA methylation, histone modifications, and microRNA expression, may play central roles in controlling changes in gene expression and genomic instability during aging. In this Hot Topic review, we first examine the mechanisms by which these epigenetic factors contribute to aging in diverse eukaryotic species including experimental models of yeasts, worms, and mammals. In a second section, we will emphasize in the mammalian epigenetic alterations and how they may affect human longevity by altering stem cell function and/or somatic cell decline. The field of aging epigenetics is ripe with potential, but is still in its infancy, as new layers of complexity are emerging in the epigenetic network. As an example, we are only beginning to understand the relevance of non-coding genome to organism aging or the existence of an epigenetic memory with transgenerational inheritance. Addressing these topics will be fundamental for exploiting epigenetics phenomena as markers of aging-related diseases or as therapeutic targets