HDAC11 is a novel drug target in carcinomas

Authors

  • Hedwig E. Deubzer,

    Corresponding author
    1. Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), Heidelberg, Germany
    2. Department of Pediatric Hematology and Oncology, University of Heidelberg, Heidelberg, Germany
    • Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
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    • Tel: ++49-6221-42-3573, Fax: ++49-6221-42-3277

  • Marie C. Schier,

    1. Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • Ina Oehme,

    1. Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • Marco Lodrini,

    1. Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • Bernard Haendler,

    1. Global Drug Discovery-TRG Oncology/GT, Bayer Pharma AG, Berlin, Germany
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  • Anette Sommer,

    1. Global Drug Discovery-TRG Oncology/GT, Bayer Pharma AG, Berlin, Germany
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  • Olaf Witt

    1. Clinical Cooperation Unit Pediatric Oncology (G340), German Cancer Research Center (DKFZ), Heidelberg, Germany
    2. Department of Pediatric Hematology and Oncology, University of Heidelberg, Heidelberg, Germany
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  • Conflicts of interest: Bernard Haendler und Anette Sommer are employees of Bayer Pharma AG and shareholders of Bayer AG.

  • Conflicts of interest: Bernard Haendler und Anette Sommer are employees of Bayer Pharma AG and shareholders of Bayer AG.

Abstract

Inhibition of histone deacetylase (HDAC) activity as stand-alone or combination therapy represents a promising therapeutic approach in oncology. The pan- or class I HDAC inhibitors (HDACi) currently approved or in clinical studies for oncology give rise to dose-limiting toxicities, presumably because of the inhibition of several HDACs. This could potentially be overcome by selective blockade of single HDAC family members. Here we report that HDAC11, the most recently identified zinc-dependent HDAC, is overexpressed in several carcinomas as compared to corresponding healthy tissues. HDAC11 depletion is sufficient to cause cell death and to inhibit metabolic activity in HCT-116 colon, PC-3 prostate, MCF-7 breast and SK-OV-3 ovarian cancer cell lines. The antitumoral effect induced can be mimicked by enforced expression of a catalytically impaired HDAC11 variant, suggesting that inhibition of the enzymatic activity of HDAC11 by small molecules could trigger the desired phenotypic changes. HDAC11 depletion in normal cells causes no changes in metabolic activity and viability, strongly suggesting that tumor-selective effects can be achieved. Altogether, our data show that HDAC11 plays a critical role in cancer cell survival and may represent a novel drug target in oncology.

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