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HR23b expression is a potential predictive biomarker for HDAC inhibitor treatment in mesenchymal tumours and is associated with response to vorinostat.

Journal article
Authors Michaela Angelika Ihle
Sabine Merkelbach-Bruse
Wolfgang Hartmann
Sebastian Bauer
Nancy Ratner
Hiroshi Sonobe
Jun Nishio
Olle Larsson
Pierre Åman
Florence Pedeutour
Takahiro Taguchi
Eva Wardelmann
Reinhard Buettner
Hans-Ulrich Schildhaus
Published in The journal of pathology. Clinical research
Volume 2
Issue 2
Pages 59-71
ISSN 2056-4538
Publication year 2016
Published at Sahlgrenska Cancer Center
Pages 59-71
Language en
Links dx.doi.org/10.1002/cjp2.35
www.ncbi.nlm.nih.gov/entrez/query.f...
Subject categories Cell and Molecular Biology, Cancer and Oncology

Abstract

Histone deacetylases (HDAC) are key players in epigenetic regulation of gene expression and HDAC inhibitor (HDACi) treatment seems to be a promising anticancer therapy in many human tumours, including soft tissue sarcomas. HR23b has been shown to be a potential biomarker for sensitivity to HDACi therapy in cutaneous T-cell lymphoma and hepatocellular carcinoma. We aimed to evaluate HR23b as a candidate biomarker for HDACi response in sarcomas and gastrointestinal stromal tumours (GIST). Therefore, HR23b expression was analysed comprehensively by western blot in sarcoma and GIST cell lines covering all major clinically relevant subtypes. MTT assay and ApoTox-Glo(TM) Triplex assay were performed after treatment with vorinostat, belinostat, mocetinostat and entinostat. HR23b protein expression was measured under HDACi treatment. Furthermore, HR23b expression levels were immunohistochemically determined in a large set of 523 clinical samples from sarcoma and GIST patients. Western blot analyses showed that sarcomas differ significantly in their expression of HR23b protein. All HDACi were able to regulate proliferation and apoptosis in vitro. Sensitivity to vorinostat correlated significantly with HR23b protein expression. Immunohistochemical prevalence screening in clinical samples of relevant adult-type tumours revealed that 12.5% of sarcomas (among them malignant peripheral nerve sheath tumours, pleomorphic liposarcomas, leiomyosarcomas, dedifferentiated liposarcomas, synovial sarcomas and angiosarcomas) and 23.2% of GIST show high HR23b expression. Therefore, HDACi have antiproliferative and proapoptotic effects in sarcomas depending on the expression level of HR23b. These findings suggest that HR23b represents a candidate biomarker for HDACi sensitivity in certain sarcoma types and in GIST.

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