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Histone Acetylation Modifiers in the Pathogenesis of Malignant Disease

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Abstract

Chromatin structure is gaining increasing attention as a potential target in the treatment of cancer. Relaxation of the chromatin fiber facilitates transcription and is regulated by two competing enzymatic activities, histone acetyltransferases (HATs) and histone deacetylases (HDACs), which modify the acetylation state of histone proteins and other promoter-bound transcription factors. While HATs, which are frequently part of multisubunit coactivator complexes, lead to the relaxation of chromatin structure and transcriptional activation, HDACs tend to associate with multisubunit corepressor complexes, which result in chromatin condensation and transcriptional repression of specific target genes. HATs and HDACs are known to be involved both in the pathogenesis as well as in the suppression of cancer. Some of the genes encoding these enzymes have been shown to be rearranged in the context of chromosomal translocations in human acute leukemias and solid tumors, where fusions of regulatory and coding regions of a variety of transcription factor genes result in completely new gene products that may interfere with regulatory cascades controlling cell growth and differentiation. On the other hand, some histone acetylation-modifying enzymes have been located within chromosomal regions that are particularly prone to chromosomal breaks. In these cases gains and losses of chromosomal material may affect the availability of functionally active HATs and HDACs, which in turn disturbs the tightly controlled equilibrium of histone acetylation. We review herein the recent achievements, which further help to elucidate the biological role of histone acetylation modifying enzymes and their potential impact on our current understanding of the molecular changes involved in the development of solid tumors and leukemias.

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Acknowledgments

We wish to apologize to those investigators whose relevant work was not discussed or cited directly in this manuscript due to space limitations. This work was partly supported by the German National Science Foundation (Deutsche Forschungsgemeinschaft, MA 2057/1-1) and institutional funds from the University of Frankfurt Medical Center.

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  1. Department of Hematology/Oncology, University of Frankfurt Medical Center, Theodor-Stern-Kai 7, D-60590, Frankfurt, Germany

    Ulrich Mahlknecht MD, PhD & Dieter Hoelzer

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  1. Ulrich Mahlknecht MD, PhD
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  2. Dieter Hoelzer
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Correspondence to Ulrich Mahlknecht MD, PhD.

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Mahlknecht, U., Hoelzer, D. Histone Acetylation Modifiers in the Pathogenesis of Malignant Disease. Mol Med 6, 623–644 (2000). https://doi.org/10.1007/BF03402044

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