Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Highlight
  • Published:

Therapeutics

It works, but how?

Nature Reviews Cancer volume 7, page 897 (2007)Cite this article

The HDACI PXD101 was used to screen a human complementary DNA (cDNA) expression library in p53-deficient mouse embryo fibroblasts (MEFs) with an oncogenic Rasv12 gene. The small numbers of infected cells that formed colonies despite exposure to PXD101 were picked and the proviral inserts were sequenced. cDNAs for the nuclear hormone receptor transcription factor RA receptor α (RARα) and the tumour antigen preferentially expressed antigen of melanoma (PRAME), which is a repressor of RA signalling, were identified in these colonies. When these cDNAs were cloned and introduced into Rasv12 MEFs they conferred resistance to PXD101 and other HDACIs of different chemical classes, although histones were still acetylated. The HDACIs were found to induce RARα transactivation, suggesting that derepression of the RA pathway is one mechanism through which HDACIs exert their anticancer activity.

The authors next asked what effect treatment with both RA and PXD101 would have on cancer cells. Mice with xenografted A375 melanoma cells and A375 cells expressing an RNA interference PRAME construct (A375–PRAMEKD) were given RA, PXD101 or both, daily. A375 tumours were fully resistant to both agents alone and combined. However, A375–PRAMEKD tumours were growth-inhibited when tumours were treated with RA and PXD101 together.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

ORIGINAL RESEARCH PAPER

  1. Epping, M. T. et al. A functional genetic screen identifies retinoic acid signaling as a target of histone deacetylase inhibitors. Proc. Natl Acad. Sci. USA 104, 17777–17782 (2007)

    Article  CAS  Google Scholar 

Download references

Authors
  1. Ezzie Hutchinson
    View author publications

    Search author on:PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hutchinson, E. It works, but how?. Nat Rev Cancer 7, 897 (2007). https://doi.org/10.1038/nrc2282

Download citation

  • Issue date:

  • DOI: https://doi.org/10.1038/nrc2282

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing