scholarly journals One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies

Epigenomes ◽  
2021 ◽  
Vol 5 (4) ◽  
pp. 22
Author(s):  
Antonia Kalushkova ◽  
Patrick Nylund ◽  
Alba Atienza Párraga ◽  
Andreas Lennartsson ◽  
Helena Jernberg-Wiklund
Keyword(s):  
Current Knowledge ◽  
Chromatin Accessibility ◽  
Response To Treatment ◽  
Haematological Malignancies ◽  
Poor Survival ◽  
Novel Treatments ◽  
Epigenetic Modifiers ◽  
Aberrant Dna Methylation ◽  
Suggested Link ◽  
Transcriptional Output

Aberrant DNA methylation, dysregulation of chromatin-modifying enzymes, and microRNAs (miRNAs) play a crucial role in haematological malignancies. These epimutations, with an impact on chromatin accessibility and transcriptional output, are often associated with genomic instability and the emergence of drug resistance, disease progression, and poor survival. In order to exert their functions, epigenetic enzymes utilize cellular metabolites as co-factors and are highly dependent on their availability. By affecting the expression of metabolic enzymes, epigenetic modifiers may aid the generation of metabolite signatures that could be utilized as targets and biomarkers in cancer. This interdependency remains often neglected and poorly represented in studies, despite well-established methods to study the cellular metabolome. This review critically summarizes the current knowledge in the field to provide an integral picture of the interplay between epigenomic alterations and the cellular metabolome in haematological malignancies. Our recent findings defining a distinct metabolic signature upon response to enhancer of zeste homolog 2 (EZH2) inhibition in multiple myeloma (MM) highlight how a shift of preferred metabolic pathways may potentiate novel treatments. The suggested link between the epigenome and the metabolome in haematopoietic tumours holds promise for the use of metabolic signatures as possible biomarkers of response to treatment.

Epigenetic Regulation and Risk Factors During the Development of Human Gametes and Early Embryos

2019 ◽  
Vol 20 (1) ◽  
pp. 21-40 ◽  
Author(s):  
Yang Wang ◽  
Qiang Liu ◽  
Fuchou Tang ◽  
Liying Yan ◽  
Jie Qiao
Keyword(s):  
Risk Factors ◽  
Embryo Development ◽  
Current Knowledge ◽  
Chromatin Accessibility ◽  
Early Embryo ◽  
Epigenetic Reprogramming ◽  
Developmental Defects ◽  
Early Embryo Development ◽  
Potential Risk Factors ◽  
Molecular Layers

Drastic epigenetic reprogramming occurs during human gametogenesis and early embryo development. Advances in low-input and single-cell epigenetic techniques have provided powerful tools to dissect the genome-wide dynamics of different epigenetic molecular layers in these processes. In this review, we focus mainly on the most recent progress in understanding the dynamics of DNA methylation, chromatin accessibility, and histone modifications in human gametogenesis and early embryo development. Deficiencies in remodeling of the epigenomes can cause severe developmental defects, infertility, and long-term health issues in offspring. Aspects of the external environment, including assisted reproductive technology procedures, parental diets, and unhealthy parental habits, may disturb the epigenetic reprogramming processes and lead to an aberrant epigenome in the offspring. Here, we review the current knowledge of the potential risk factors of aberrant epigenomes in humans.

scholarly journals SOX9 Stem-Cell Factor: Clinical and Functional Relevance in Cancer

2019 ◽  
Vol 2019 ◽  
pp. 1-16 ◽  
Author(s):  
Maribel Aguilar-Medina ◽  
Mariana Avendaño-Félix ◽  
Erik Lizárraga-Verdugo ◽  
Mercedes Bermúdez ◽  
José Geovanni Romero-Quintana ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Stem Cell Factor ◽  
Current Knowledge ◽  
Functional Roles ◽  
Novel Treatments ◽  
Specific Subset ◽  
Different Types ◽  
Undifferentiated Cells ◽  
Functional Relevance

Transcriptional and epigenetic embryonic programs can be reactivated in cancer cells. As result, a specific subset of undifferentiated cells with stem-cells properties emerges and drives tumorigenesis. Recent findings have shown that ectoderm- and endoderm-derived tissues continue expressing stem-cells related transcription factors of the SOX-family of proteins such as SOX2 and SOX9 which have been implicated in the presence of cancer stem-like cells (CSCs) in tumors. Currently, there is enough evidence suggesting an oncogenic role for SOX9 in different types of human cancers. This review provides a summary of the current knowledge about the involvement of SOX9 in development and progression of cancer. Understanding the functional roles of SOX9 and clinical relevance is crucial for developing novel treatments targeting CSCs in cancer.

scholarly journals Novel Approaches to Target Mutant FLT3 Leukaemia

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2806
Author(s):  
Jörg P. Müller ◽  
Dirk Schmidt-Arras
Keyword(s):  
Tyrosine Kinases ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Class Iii ◽  
Poor Survival ◽  
Efficient Treatment ◽  
Oncogenic Mutations ◽  
Proliferation And Differentiation ◽  
Current Therapies ◽  
Novel Therapeutic Strategies

Fms-like tyrosine kinase 3 (FLT3) is a member of the class III receptor tyrosine kinases (RTK) and is involved in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Oncogenic mutations in the FLT3 gene resulting in constitutively active FLT3 variants are frequently found in acute myeloid leukaemia (AML) patients and correlate with patient’s poor survival. Targeting FLT3 mutant leukaemic stem cells (LSC) is a key to efficient treatment of patients with relapsed/refractory AML. It is therefore essential to understand how LSC escape current therapies in order to develop novel therapeutic strategies. Here, we summarize the current knowledge on mechanisms of FLT3 activity regulation and its cellular consequences. Furthermore, we discuss how aberrant FLT3 signalling cooperates with other oncogenic lesions and the microenvironment to drive haematopoietic malignancies and how this can be harnessed for therapeutical purposes.

scholarly journals FAM3C: an emerging biomarker and potential therapeutic target for cancer

2021 ◽  
Author(s):  
Yuanyuan Zhu ◽  
Zhangya Pu ◽  
Guoqiang Wang ◽  
Yubin Li ◽  
Yinmiao Wang ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Subcellular Localization ◽  
Therapeutic Target ◽  
Current Knowledge ◽  
Expression Patterns ◽  
Tumor Formation ◽  
Cancer Development ◽  
Poor Survival ◽  
Potential Therapeutic Target ◽  
Regulatory Functions

FAM3C is a member of the FAM3 family. Recently, overexpression of FAM3C has been reported in numerous types of cancer, including breast and colon cancer. Increasing evidence suggests that elevated FAM3C and its altered subcellular localization are closely associated with tumor formation, invasion, metastasis and poor survival. Moreover, FAM3C has been found to be the regulator of various proteins that associate with cancer, including Ras, STAT3, TGF-β and LIFR. This review summarizes the current knowledge regarding FAM3C, including its structure, expression patterns, regulation, physiological roles and regulatory functions in various malignancies. These findings highlight the importance of FAM3C in cancer development and provide evidence that FAM3C is a novel biomarker and potential therapeutic target for various cancers.

scholarly journals Pparα and fatty acid oxidation coordinate hepatic transcriptional architecture

2021 ◽  
Author(s):  
Kyle S Cavagnini ◽  
Michael J Wolfgang
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Chromatin Accessibility ◽  
Lipid Homeostasis ◽  
Acid Oxidation ◽  
Binding Motifs ◽  
Hepatic Fatty Acid ◽  
Glucose And Lipid Homeostasis ◽  
Hepatic Fatty Acid Oxidation ◽  
Transcriptional Output

Fasting requires tight coordination between the metabolism and transcriptional output of hepatocytes to maintain systemic glucose and lipid homeostasis. Deficits in hepatic fatty acid oxidation result in dramatic fasting-induced hepatocyte lipid accumulation and induction of genes for oxidative metabolism that are largely driven by Pparα. While fatty acid oxidation is required for a rise in acetyl-CoA and subsequent lysine acetylation following a fast, changes in histone acetylation (total, H3K9ac, and H3K27ac) do not require fatty acid oxidation. Active enhancers in fasting mice are enriched for Pparα binding motifs. Genetically-defined inhibition of hepatic fatty acid oxidation results in higher levels of chromatin accessibility as well as elevated enhancer priming and acetylation proximal to Pparα sites largely associated with genes in lipid metabolism. Also, greater number of Pparα-associated H3K27ac signal changes occur at active enhancers compared to promoters, suggesting a mechanism for Pparα to tune target expression levels at pre-primed sites. Overall, these data show the requirement for Pparα activation in maintaining transcriptionally permissive hepatic genomic architecture particularly when fatty acid oxidation is limiting.

scholarly journals Characteristics, correlates, and outcomes of childhood and adolescent depressive disorders

2009 ◽  
Vol 11 (1) ◽  
pp. 45-62 ◽  
Keyword(s):  
Children And Adolescents ◽  
Depressive Disorders ◽  
Current Knowledge ◽  
Unipolar Depression ◽  
Depressive Illness ◽  
Developmental Differences ◽  
Natural Course ◽  
Response To Treatment ◽  
Childhood And Adolescence ◽  
Full Potential

Depressive illness beginning early in life can have serious developmental and functional consequences. Therefore, understanding the disorder during this developmental stage is critical for determining its etiology and course, as well as for developing effective intervention strategies. This paper summarizes current knowledge regarding the etiology, phenomenology, correlates, natural course, and consequences of unipolar depression in children and adolescents. Using adult depression as a framework, the unique aspects of childhood and adolescence are considered in order to better understand depression within a developmental context. The data suggest that the clinical presentation, correlates, and natural course of depression are remarkably similar across the lifespan. There are, however, important developmental differences. Specifically, the familial and psychological context in which depression develops in youngsters is associated with variability in the frequency and nature of depressive symptoms and comorbid conditions among children and adolescents. Maturational differences have also been identified in the neurobiological correlates of depression. These developmental differences may be associated with the observed variability in clinical response to treatment and longitudinal course. Characterization of the developmental differences will be helpful in developing more specific and effective interventions for youngsters, thereby allowing them to reach their full potential as adults.

Outcomes of High-Dose Steroid Therapy for Infantile Spasms in Children With Trisomy 21

2019 ◽  
Vol 34 (11) ◽  
pp. 646-652 ◽  
Author(s):  
Dallas Armstrong ◽  
Rana R. Said
Keyword(s):  
Trisomy 21 ◽  
Current Knowledge ◽  
Significant Proportion ◽  
Retrospective Chart Review ◽  
Infantile Spasms ◽  
Response To Treatment ◽  
Pediatric Epilepsy ◽  
High Dose ◽  
First Line ◽  
Clinical Onset

Objective: We performed a retrospective chart review of patients with trisomy 21 and infantile spasms in our university-based pediatric epilepsy center between 2002 and 2016 in order to describe the clinical characteristics of children with these diagnoses as well as to evaluate their response to first-line treatments. Methods: Patients with infantile spasms were identified via the neurophysiology database. Charts were reviewed with attention to infantile spasms diagnosis, presence of trisomy 21, age of reported clinical onset, treatment lag, treatments used, response to treatment, imaging findings, electroencephalography (EEG) data, and developmental outcomes. Results: Of the 310 patients with infantile spasms, 24 also had trisomy 21. Three patients did not meet inclusion criteria. Ten of the 21 patients received nonstandard therapies first line; 2 of the 10 (20%) achieved spasm control, and 4 of the 8 who failed therapy (50%) progressed to Lennox-Gastaut syndrome. Eleven of the 21 patients received standard therapies as first-line treatments (10 with prednisolone according to the protocol in the United Kingdom Infantile Spasms Study [UKISS] and 1 with adrenocorticotrophic hormone [ACTH]). Nine of the 10 patients (90%) who received prednisolone achieved spasm resolution, 6 (60%) of these without relapse. The final patient (10%) failed prednisolone as well as ACTH. One patient received ACTH first line with success. Conclusion: This is the only series to follow children with trisomy 21 and infantile spasms in which a significant proportion received UKISS-protocol prednisolone. It adds to current knowledge about safety, tolerability, and effectiveness of prednisolone in this group.

CSNK2 in cancer: Pathophysiology and translational applications.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15594-e15594
Author(s):  
Scott Strum ◽  
Laszlo Gyenis ◽  
David W Litchfield
Keyword(s):  
Current Knowledge ◽  
Human Cancer ◽  
Prognostic Significance ◽  
Response To Treatment ◽  
In Vivo Studies ◽  
Protein Activity ◽  
Oncology Research ◽  
Wide Range

e15594 Background: Protein kinase CSNK2 (CK2) is a pleiotropic serine/threonine kinase whose expression levels are frequently elevated in solid and hematologic malignancies. CSNK2 has been discovered to hold prognostic and therapeutic significance across multiple cancers and is an excellent target for oncology research. This systematic review summarizes the current knowledge from in vitro and in vivo studies on the biology of this kinase in cancer alongside pre-clinical/clinical investigations from 24 different human cancer types. Methods: PRISMA methodology was used to generate a study protocol and building-block search strategy, from which a total of 796 publications in PubMed were retrieved across 24 human cancers. 245 of these publications met both screening and inclusion criteria. Data was then systematically extracted, including information about CSNK2 subunit mRNA/protein/activity levels, phosphorylation targets, phenotypic changes, in vivo studies, and prognostic/therapeutic data. The data was thereafter summarized and analyzed. Results: Five targets phosphorylated by CSNK2 were identified in at least 4 cancers: AKT, STAT3, RELA, PTEN, and TP53. The most heavily cited was AKT, identified in 15 cancers. Phenotypically, behaviors influenced by CSNK2 that were reported in 11 or more cancers included: evasion of apoptosis, enhancement of proliferation, enhancement of invasion/metastasis, and cell cycle control. Interestingly, these pathways correlated heavily with the most commonly cited CSNK2 targets. From a clinical perspective, CSNK2 held prognostic significance in 17 of the cancers. Additionally, xenograft experiments were found to have been performed in 13 cancers where CSNK2 inhibition resulted in a positive response to treatment. Lastly, early studies have shown promising results through the clinical application of CSNK2-specific inhibitors, with several clinical trials now underway for further assessment. Conclusions: Overall, our analysis supports CSNK2 as an attractive target for cancer therapy and points to specific areas where additional investigation is critical to advance our understanding of CSNK2 biology. The design of targeted therapies by exploiting the pathophysiology of CSNK2 has the potential to generate impactful treatment strategies across a wide range of cancers, promising exciting new discoveries scientifically and clinically.

Abstract 14745: The Histone Reader PHF7 Cooperates With the SWI/SNF Complex at Cardiac Super Enhancers to Promote Direct Cardiac Reprogramming

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Glynnis A Garry ◽  
Svetlana Bezprozvannaya ◽  
Kenian Chen ◽  
Huanyu Zhou ◽  
Hisayuki Hashimoto ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Chromatin Remodeling ◽  
Therapeutic Strategy ◽  
Chromatin Accessibility ◽  
Epigenetic Factor ◽  
Epigenetic Modifiers ◽  
Regulatory Circuit ◽  
Gene Regulatory ◽  
Cardiac Transcription Factors ◽  
Adult Fibroblasts

Direct cardiac reprogramming of fibroblasts to cardiomyocytes presents an attractive therapeutic strategy to restore cardiac function following injury. Cardiac reprogramming was initially achieved through the overexpression of the transcription factors Gata4, Mef2c, and Tbx5 (GMT), and later, Hand2 (GHMT) and Akt1 (AGHMT) were found to further enhance this process. Yet, staunch epigenetic barriers severely limit the ability of these cocktails to reprogram adult fibroblasts. We undertook a screen of mammalian gene regulatory factors to discover novel regulators of cardiac reprogramming in adult fibroblasts and identified the histone reader PHF7 as the most potent activating factor. Mechanistically, PHF7 localizes to cardiac super enhancers in fibroblasts, and through cooperation with the SWI/SNF complex, increases chromatin accessibility and transcription factor binding at these sites. Further, PHF7 recruits cardiac transcription factors to activate a core regulatory circuit in reprogramming. Importantly, PHF7 is the first epigenetic factor shown to achieve efficient reprogramming in the absence of Gata4. Here, we highlight the underexplored necessity of cardiac epigenetic modifiers, such as PHF7, in harnessing chromatin remodeling and transcriptional complexes to overcome critical barriers to direct cardiac reprogramming.

scholarly journals Translational Potential of MicroRNAs for Preoperative Staging and Prediction of Chemoradiotherapy Response in Rectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1545 ◽  
Author(s):  
Machackova ◽  
Prochazka ◽  
Kala ◽  
Slaby
Keyword(s):  
Colorectal Cancer ◽  
Rectal Cancer ◽  
Cancer Patients ◽  
Current Knowledge ◽  
Preoperative Staging ◽  
Operative Therapy ◽  
Tnm Staging ◽  
Response To Therapy ◽  
Response To Treatment ◽  
Circulating Mirnas

Abstract: Colorectal cancer is the third most common cancer and the second cause of cancer-related deaths. Rectal cancer presents roughly one-third of all colorectal cancer cases and differs from it on both anatomical and molecular levels. While standard treatment of colon cancer patients is radical surgery, rectal cancer is usually treated with pre-operative chemoradiotherapy followed by total mesorectal excision, which requires precise estimation of TNM staging. Unfortunately, stage evaluation is based solely on imaging modalities, and they often do not correlate with postoperative pathological findings. Moreover, approximately half of rectal cancer patients do not respond to such pre-operative therapy, so they are exposed to its toxic effects without any clinical benefit. Thus, biomarkers that could precisely predict pre-operative TNM staging, and especially response to therapy, would significantly advance rectal cancer treatment—but till now, no such biomarker has been identified. In cancer research, microRNAs are emerging biomarkers due to their connection with carcinogenesis and exceptional stability. Circulating miRNAs are promising non-invasive biomarkers that could allow monitoring of a patient throughout the whole therapeutic process. This mini-review aims to summarize the current knowledge on miRNAs and circulating miRNAs involved in the prediction of response to treatment and pre-operative staging in rectal cancer patients.

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