21
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      HDAC Inhibitors Disrupt Programmed Resistance to Apoptosis During Drosophila Development

      research-article

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          We have previously shown that the ability to respond to apoptotic triggers is regulated during Drosophila development, effectively dividing the fly life cycle into stages that are either sensitive or resistant to apoptosis. Here, we show that the developmentally programmed resistance to apoptosis involves transcriptional repression of critical proapoptotic genes by histone deacetylases (HDACs). Administration of HDAC inhibitors (HDACi), like trichostatin A or suberoylanilide hydroxamic acid, increases expression of proapoptotic genes and is sufficient to sensitize otherwise resistant stages. Conversely, reducing levels of proapoptotic genes confers resistance to otherwise sensitive stages. Given that resistance to apoptosis is a hallmark of cancer cells, and that HDACi have been recently added to the repertoire of FDA-approved agents for cancer therapy, our results provide new insights for how HDACi help kill malignant cells and also raise concerns for their potential unintended effects on healthy cells.

          Most cited references29

          • Record: found
          • Abstract: found
          • Article: not found

          Identification of functional elements and regulatory circuits by Drosophila modENCODE.

          To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Intrinsic tumour suppression.

            Mutations that drive uncontrolled cell-cycle progression are requisite events in tumorigenesis. But evolution has installed in the proliferative programmes of mammalian cells a variety of innate tumour-suppressive mechanisms that trigger apoptosis or senescence, should proliferation become aberrant. These contingent processes rely on a series of sensors and transducers that act in a coordinated network to target the machinery responsible for apoptosis and cell-cycle arrest at different points. Although oncogenic mutations that disable such networks can have profound and varied effects on tumour evolution, they may leave intact latent tumour-suppressive potential that can be harnessed therapeutically.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Dimethyl sulfoxide to vorinostat: development of this histone deacetylase inhibitor as an anticancer drug.

              In our quest to understand why dimethyl sulfoxide (DMSO) can cause growth arrest and terminal differentiation of transformed cells, we followed a path that led us to discover suberoylanilide hydroxamic acid (SAHA; vorinostat (Zolinza)), which is a histone deacetylase inhibitor. SAHA reacts with and blocks the catalytic site of these enzymes. Extensive structure-activity studies were done along the path from DMSO to SAHA. SAHA can cause growth arrest and death of a broad variety of transformed cells both in vitro and in tumor-bearing animals at concentrations not toxic to normal cells. SAHA has many protein targets whose structure and function are altered by acetylation, including chromatin-associated histones, nonhistone gene transcription factors and proteins involved in regulation of cell proliferation, migration and death. In clinical trials, SAHA has shown significant anticancer activity against both hematologic and solid tumors at doses well tolerated by patients. A new drug application was approved by the US Food and Drug Administration for vorinostat for treatment of cutaneous T-cell lymphoma. More potent analogs of SAHA have shown unacceptable toxicity.
                Bookmark

                Author and article information

                Journal
                G3 (Bethesda)
                Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes|Genomes|Genetics
                Genetics Society of America
                2160-1836
                27 April 2017
                June 2017
                : 7
                : 6
                : 1985-1993
                Affiliations
                [* ]Division of Pharmaceutical Sciences, University of Wisconsin-Madison, Wisconsin 53705-2222
                []Laboratory of Genetics Graduate Program, University of Wisconsin-Madison, Wisconsin 53705-2222
                Author notes
                [1]

                These authors contributed equally to this work.

                [2]

                Present address: Vollum Institute, Oregon Health & Sciences University, Portland, OR 97239.

                [3]

                Present address: Developmental, Regenerative, and Stem Cell Program, Washington University in St. Louis, MO 63130.

                [4 ]Corresponding author: Division of Pharmaceutical Sciences, University of Wisconsin-Madison, 777 Highland Avenue, Madison, WI 53705-2222. E-mail: bashirullah@ 123456wisc.edu
                Article
                GGG_041541
                10.1534/g3.117.041541
                5473774
                28455414
                48a369cd-b4dc-4113-9e55-158ce3432a48
                Copyright © 2017 Kang et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 March 2017
                : 26 April 2017
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 39, Pages: 9
                Categories
                Investigations

                Genetics
                apoptotic thresholds,caspase activation,tsa,saha,hdac1/rpd3
                Genetics
                apoptotic thresholds, caspase activation, tsa, saha, hdac1/rpd3

                Comments

                Comment on this article