Correspondence in Nature Genetics by Ree, Folkvord, and Flatmark

Anne Hansen Ree (left), Sigurd Folkvord and Kjersti Flatmark
Anne Hansen Ree (left), Sigurd Folkvord and Kjersti Flatmark

Professor Anne Hansen Ree and coauthors Sigurd Folkvord and Kjersti Flatmark from Department of Tumor Biology are publishing a correspondence, entitled “HDAC2 deficiency and histone acetylation”, in the July 2008 issue of Nature Genetics. The authors report the effects of combining trichostatin A (TSA) with radiation in HDAC2-deficient colorectal carcinoma cells.

Methylation of DNA has been studied through the recent decades as a prototype epigenetic phenomenon, typically being dysregulated in malignant processes. Recently, modifications of histones have gained increasing attention in understanding key regulatory processes in malignancy and tumor response to therapy.


HISTONE DEACETYLASE (HDAC) INHIBITION – HISTONE ACETYLATION
DNA (purple) is wound around a core of histones (blue) to form the nucleosome, the smallest structural unit of chromatin. Nucleosomal histones are subject to acetylation (acetyl groups in green) by histone acetyltransferases (HAT), which is associated with an open state of the chromatin. By this modification, correspondingly resulting from HDAC inhibition, DNA becomes transcriptionally active and, in theory, more vulnerable to damage.

Inhibition of HDAC activity causes histone hyperacetylation. Currently, a dozen HDAC inhibitors are under investigation in clinical trials, and suberoylanilide hydroxamic acid (SAHA, vorinostat) was recently US approved as single-agent therapeutic. Reports indicating low toxicity and favorable safety profiles suggest HDAC inhibitors also as interesting candidates for combinatory regimens with cytotoxic therapy (radiotherapy, chemotherapy).

Radiotherapy is a central therapeutic modality in curative treatment of rectal cancer and also as palliative treatment in patients with advanced colorectal cancer disease. The principal therapeutic intent of exposing tumor cells to ionizing radiation is to produce irreversible DNA damage that induces mitotic catastrophe and subsequent tumor cell death. With current advances in clinical radiotherapy, strategies for improving therapeutic efficacy are increasingly focused on targeting molecular mechanisms to increase tumor cell radiosensitivity, and HDAC inhibition is emerging as a promising concept.

The authors have previously reported on tumor cell radiosensitization in human colorectal carcinoma cell lines treated with SAHA and have recently observed increased radiation response of human colorectal carcinoma xenografts on treating the tumor-bearing mice with SAHA. In an ongoing clinical trial (the PRAVO study; Pelvic Radiation and Vorinostat), SAHA is combined with palliative radiotherapy for advanced pelvic tumors, mainly colorectal cancers [ClinicalTrials.gov Id. NCT00455351]. The EPI-ART program (EPIgenomics in Advanced RadioTherapy) is intended to reveal regulatory mechanisms responsible for the radiosensitizing effect of HDAC inhibition and to identify molecular markers for prediction of therapeutic efficacy, using the experimental in vivo models (colorectal carcinoma xenografts) and validating the experimental findings in tumor biopsy specimens obtained from the PRAVO trial.

It was previously suggested that tumor HDAC2 deficiency might impair the therapeutic response to HDAC inhibitors [Ropero et al., Nat Genet 2006; 38, 566-9]. In the current correspondence, the authors show that the HDAC inhibitor TSA induced histone hyperacetylation in human colorectal carcinoma cells harboring defective HDAC2. Also, tumor cells were sensitized by TSA to ionizing radiation, as assessed by clonogenic survival, irrespective of HDAC2 status, implying that loss of HDAC2 function may not alter tumor response to HDAC inhibitors in radiotherapy.

By: Anne Hansen Ree, Sigurd Folkvord and Kjersti Flatmark

 

Link to the article (from PubMed):

Ree AH, Folkvord S, Flatmark K.
HDAC2 deficiency and histone acetylation.
Nat Genet. 2008 Jul;40(7):812-3; author reply 813.