HDAC2 mediates therapeutic resistance of pancreatic cancer cells via the BH3-only protein NOXA
- 1Technische Universität München, Klinikum rechts der Isar, II Medizinische Klinik, Munich, Germany
- 2Technische Universität München, Lehrstuhl für Biotechnologie der Nutztiere, Freising, Germany
- 3Helmholtz Zentrum München, Institut für Toxikologie, Neuherberg, Germany
- Correspondence to Dr G Schneider, Technische Universität München, Klinikum rechts der Isar, II Medizinische Klinik, Ismaninger Str 22, 81675 Munich, Germany;
- Revised 19 May 2009
- Accepted 1 June 2009
- Published Online First 14 June 2009
Background: Although histone deacetylase inhibitors (HDACi) are promising cancer therapeutics regulating proliferation, differentiation and apoptosis, molecular pathways engaged by specific HDAC isoenzymes in cancer are ill defined.
Results: In this study we demonstrate that HDAC2 is highly expressed in pancreatic ductal adenocarcinoma (PDAC), especially in undifferentiated tumours. We show that HDAC2, but not HDAC1, confers resistance towards the topoisomerase II inhibitor etoposide in PDAC cells. Correspondingly, the class I selective HDACi valproic acid (VPA) synergises with etoposide to induce apoptosis of PDAC cells. Transcriptome profiling of HDAC2-depleted PDAC cells revealed upregulation of the BH3-only protein NOXA. We show that the epigenetically silenced NOXA gene locus is opened after HDAC2 depletion and that NOXA upregulation is sufficient to sensitise PDAC cells towards etoposide-induced apoptosis.
Conclusions: In summary, our data characterise a novel molecular mechanism that links the epigenetic regulator HDAC2 to the regulation of the pro-apoptotic BH3-only protein NOXA in PDAC. Targeting HDAC2 will therefore be a promising strategy to overcome therapeutic resistance of PDAC against chemotherapeutics that induce DNA damage.
Funding DFG (Grant SCHN 959/1-1) and Else Kröner-Fresenius Stiftung (Grant A130/07).
Competing interests None.
Provenance and Peer review Not commissioned; externally peer reviewed.
▸ Four supplementary figures are published online only at http://gut.bmj.com/content/vol58/issue10