title: HR23b expression is a potential predictive biomarker for HDAC inhibitor treatment in mesenchymal tumours and is associated with response to vorinostat.
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.
authors: Institute of Pathology, University Hospital Cologne Cologne Germany.
authors: Michaela
authors: M
authors: Angelika Ihle
authors: Institute of Pathology, University Hospital Cologne Cologne Germany.
authors: Sabine
authors: S
authors: Merkelbach-Bruse
authors: Institute of Pathology, University Hospital CologneCologneGermany; Gerhard Domagk Institute of Pathology, University Hospital MünsterMünsterGermany.
authors: Wolfgang
authors: W
authors: Hartmann
authors: Sarcoma Center, West German Cancer Center, University of Essen Essen Germany.
authors: Sebastian
authors: S
authors: Bauer
authors: US Department of Pediatrics Cincinnati Children's Hospital Medical Centre Cincinnati OH USA.
authors: Nancy
authors: N
authors: Ratner
authors: Department of Laboratory Medicine Chugoku Central Hospital Fukuyama Hiroshima Japan.
authors: Hiroshi
authors: H
authors: Sonobe
authors: Faculty of Medicine, Department of Orthopaedic Surgery Fukuoka University Fukuoka Japan.
authors: Jun
authors: J
authors: Nishio
authors: Department of Oncology and Pathology The Karolinska Institute Stockholm Sweden.
authors: Olle
authors: O
authors: Larsson
authors: Sahlgrenska Cancer Centre, University of Gothenburg Gothenburg Sweden.
authors: Pierre
authors: P
authors: Åman
authors: Faculty of Medicine, Laboratory of Genetics of Solid Tumours Institute for Research on Cancer and Aging Nice France.
authors: Florence
authors: F
authors: Pedeutour
authors: Division of Human Health & Medical Science, Graduate School of Kuroshio Science Kochi University Nankoku Kochi Japan.
authors: Takahiro
authors: T
authors: Taguchi
authors: Institute of Pathology, University Hospital CologneCologneGermany; Gerhard Domagk Institute of Pathology, University Hospital MünsterMünsterGermany.
authors: Eva
authors: E
authors: Wardelmann
authors: Institute of Pathology, University Hospital Cologne Cologne Germany.
authors: Reinhard
authors: R
authors: Buettner
authors: Institute of Pathology, University Hospital CologneCologneGermany; Institute of Pathology, University Hospital GöttingenGöttingenGermany.
authors: Hans-Ulrich
authors: HU
authors: Schildhaus
keywords: GIST; HDACi; HR23b; RAD23b; Sarcoma; biomarker