https://www.ncbi.nlm.nih.gov/pubmed/31172592
J Cell Biochem. 2019 Jun 6. doi: 10.1002/jcb.29147. [Epub ahead of print]
Quercetin
modifies 5'CpG promoter methylation and reactivates various tumor
suppressor genes by modulating epigenetic marks in human cervical cancer
cells.Abstract
The central role of epigenomic alterations in carcinogenesis has been widely acknowledged, particularly the impact of DNA methylation on gene expression across all stages of carcinogenesis is considered vital for both diagnostic and therapeutic strategies. Dietary phytochemicals hold great promise as safe anticancer agents and effective epigenetic modulators. This study was designed to investigate the potential of a phytochemical, quercetin as a modulator of the epigenetic pathways for anticancer strategies. Biochemical activity of DNA methyltransferases (DNMTs), histone deacetylases (HDACs), histone methyltransferases (HMTs), and global genomic DNA methylation was quantitated by an enzyme-linked immunosorbent assay based assay in quercetin-treated HeLa cells. Molecular docking studies were performed to predict the interaction of quercetin with DNMTs and HDACs. Quantitative methylation array was used to assess quercetin-mediated alterations in the promoter methylation of selected tumor suppressor genes (TSGs). Quercetin induced modulation of chromatin modifiers including DNMTs, HDACs, histone acetyltransferases (HAT) and HMTs, and TSGs were assessed by quantitative reverse transcription PCR (qRT-PCR). It was found that quercetin modulates the expression of various chromatin modifiers and decreases the activity of DNMTs, HDACs, and HMTs in a dose-dependent manner. Molecular docking results suggest that quercetin could function as a competitive inhibitor by interacting with residues in the catalytic cavity of several DNMTs and HDACs. Quercetin downregulated global DNA methylation levels in a dose- and time-dependent manner. The tested TSGs showed steep dose-dependent decline in promoter methylation with the restoration of their expression. Our study provides an understanding of the quercetin's mechanism of action and will aid in its development as a candidate for epigenetic-based anticancer therapy.
A Class II Histone Deacetylase Acts on Newly Synthesized Histones in ...
https://ec.asm.org/content/7/3/471
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av JJ Smith - 2008 - Citerat av 12 - Relaterade artiklar
Most systems share the difficulty of separating chromatin maturation-related from ..... Thd2 is a class II HDAC with a putative IPK domain similar to Ipk2.
Kommentti: ...hiivan . (ArgRIII) ..ihmisellä IPKL domeeni, joka on arginiinipitoinen , IP6K2 entsyymin domeeni.
Front Oncol. 2019 May 22;9:432. doi: 10.3389/fonc.2019.00432. eCollection 2019. Intersection of Epigenetic and Metabolic Regulation of Histone Modifications in Acute Myeloid Leukemia.
Acute
myeloid leukemia (AML) is one of the most lethal blood cancers,
accounting for close to a quarter of a million annual deaths worldwide.
Even though genetically heterogeneous, all AMLs are characterized by two
interrelated features-blocked differentiation and high proliferative
capacity. Despite significant progress in our understanding of the
molecular and genetic basis of AML, the treatment of AMLs with
chemotherapeutic regimens has remained largely unchanged in the past 30
years. In this review, we will consider the role of two cellular
processes, metabolism and epigenetics, in the development and
progression of AML and highlight the studies that suggest an
interconnection of therapeutic importance between the two. Large-scale
whole-exome sequencing of AML patients has revealed the presence of
mutations, translocations or duplications in several epigenetic
effectors such as DNMT3, MLL, ASXL1, and TET2, often times co-occuring
with mutations in metabolic enzymes such as IDH1 and IDH2. These
mutations often result in impaired enzymatic activity which leads to an
altered epigenetic landscape through dysregulation of chromatin
modifications such as DNA methylation, histone
acetylation and methylation. We will discuss the role of enzymes that
are responsible for establishing these modifications, namely histone acetyl transferases (HAT), histone methyl transferases (HMT), demethylases (KDMs), and deacetylases
(HDAC), and also highlight the merits and demerits of using inhibitors
that target these enzymes. Furthermore, we will tie in the metabolic
regulation of co-factors such as acetyl-CoA, SAM, and α-ketoglutarate
that are utilized by these enzymes and examine the role of metabolic
inhibitors as a treatment option for AML. In doing so, we hope to
stimulate interest in this topic and help generate a rationale for the
consideration of the combinatorial use of metabolic and epigenetic
inhibitors for the treatment of AML. KEYWORDS:
AML—acute myeloid leukaemia; HDACs; epigenetics (methylation/demethylation); histone methlyation; metabolism
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