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Related Concept Videos

Epigenetic Regulation01:37

Epigenetic Regulation

Epigenetic changes alter the physical structure of the DNA without changing the genetic sequence and often regulate whether genes are turned on or off. This regulation ensures that each cell produces only proteins necessary for its function. For example, proteins that promote bone growth are not produced in muscle cells. Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
X-chromosome...
Epigenetic Regulation01:46

Epigenetic Regulation

Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
Epigenetic Regulation01:46

Epigenetic Regulation

Epigenetic mechanisms play an essential role in healthy development. Conversely, precisely regulated epigenetic mechanisms are disrupted in diseases like cancer.
Histone Modification02:32

Histone Modification

The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Histone Modification02:32

Histone Modification

The histone proteins have a flexible N-terminal tail extending out from the nucleosome. These histone tails are often subjected to post-translational modifications such as acetylation, methylation, phosphorylation, and ubiquitination. Particular combinations of these modifications form “histone codes” that influence the chromatin folding and tissue-specific gene expression.
Acetylation
The enzyme histone acetyltransferase adds acetyl group to the histones. Another enzyme, histone deacetylase,...
Eukaryotic Transcription Inhibitors01:52

Eukaryotic Transcription Inhibitors

Certain biochemical processes, such as embryonic development and cell growth regulation, depend on the repression of specific genes. DNA binding proteins known as eukaryotic transcription inhibitors regulate the repression of gene expression in eukaryotes. The presence of these inhibitors at the required location and time in the cell is triggered by the presence of hormones and additional signals from other cells.
Eukaryotic transcription inhibitors usually contain two distinct domains, a DNA...

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Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers
10:28

Repressing Gene Transcription by Redirecting Cellular Machinery with Chemical Epigenetic Modifiers

Published on: September 20, 2018

Polyamine analogues targeting epigenetic gene regulation.

Yi Huang1, Laurence J Marton, Patrick M Woster

  • 1The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. rcasero@jhmi.edu

Essays in Biochemistry
|January 26, 2010
PubMed
Summary

Polyamines are explored for cancer therapy by targeting chromatin remodelling enzymes like HDACs and LSD1. Novel polyamine analogues show promise in inhibiting these enzymes, leading to tumor growth inhibition and gene re-activation for cancer treatment.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Polyamines are crucial for DNA stabilization and RNA processing, influencing gene expression.
  • Their role in chromatin regulation makes them attractive targets for antineoplastic therapy.
  • Novel proteins homologous to polyamine metabolism enzymes have been identified, opening new therapeutic avenues.

Purpose of the Study:

  • To explore chromatin remodelling enzymes as therapeutic targets for polyamine analogues.
  • To develop novel polyamine-based inhibitors for cancer treatment.
  • To investigate the efficacy of polyamine analogues against histone deacetylases (HDACs) and lysine-specific demethylase 1 (LSD1).

Main Methods:

  • Synthesized polyaminohydroxamic acids (PAHAs) and polyaminobenzamides (PABAs) as HDAC inhibitors.
  • Identified polyamine analogues targeting flavin-dependent lysine-specific demethylase 1 (LSD1).
  • Assessed inhibition of HDACs and LSD1, p21 re-expression, tumor growth inhibition, and epigenetic gene reactivation.

Main Results:

  • PAHAs and PABAs potently inhibited HDACs, re-expressed p21, and significantly inhibited tumor growth.
  • Biguanide, bisguanidine, and oligoamine polyamine analogues effectively inhibited LSD1.
  • Cellular inhibition of LSD1 reactivated epigenetically silenced genes crucial in tumorigenesis.

Conclusions:

  • Novel polyamine-based inhibitors of HDACs and LSD1 represent a promising approach for cancer prevention and therapy.
  • Targeting chromatin remodelling enzymes with polyamine analogues offers a new strategy in oncology.
  • These findings highlight the therapeutic potential of manipulating polyamine interactions with chromatin-modifying enzymes.