Abstract 1830: Both class I and class II histone deacetylases are required for proliferation and survival of human pancreatic cancer cells

Abstract

Abstract Pancreatic cancer is a highly malignant disease whose incidence has risen steadily and it is now the fourth leading cause of death from cancer in the western world. Due to delays in clinical diagnosis, pancreatic cancer is often detected at an advanced stage and the prognosis is extremely poor. Thus, pancreatic cancer remains a highly chemoresistant malignancy that urgently requires new therapeutic targets. Histone deacetylases (HDACs) play important roles in the epigenetic regulation of gene expression and have been suggested to play important roles in the pathogenesis of pancreatic cancer. Numerous small molecule HDAC inhibitors (HDACIs) have been developed during the last decade, which have shown promising antitumor activities against pancreatic cancer in preclinical models either alone or in combination with gemcitabine. However, the most clinically relevant HDAC isoforms have not been identified. In this study, we sought to investigate the roles of classes I and II HDACs in proliferation and survival of human pancreatic cancer cell lines. Western blotting revealed expression of the majority of class I and class II HDACs in three pancreatic cell lines, PANC-1, BxPC-3, and AsPC-1, though the levels were albeit variable. Treatments with the novel pan-HDACI, Panobinostat (LBH589), resulted in dose-dependent inhibition of cell proliferation and induction of cell death (apoptosis) along with cell cycle arrest in G2/M phase. Essentially the same results were obtained with the novel class I-selective inhibitor, MGCD0103, though to a much lesser extent. In contrast, MC1568 (a class IIa-specific inhibitor) and Tubastatin A (a HDAC6-specific inhibitor), only showed minimal effects on cell proliferation, cell death, apoptosis, and cell cycle distribution. Interestingly, when combined simultaneously, MC1568 synergistically enhanced MGCD0103-mediated inhibition of cell proliferation and induction of cell death, apoptosis, and cell cycle arrest in G2/M phase. In contrast, Tubastatin A synergistically enhanced MGCD0103-induced proliferation arrest only. Both Panobinostat and MGCD0103 treatments resulted in induction of p21 and DNA double strand breaks (DSBs), reflected in the induction of γH2AX (a biomarker of DNA DSBs), and suppression of checkpoint kinase 1 (CHK1). In contrast, MC1568 and Tubastatin A had no obvious effects on the expression of these proteins. Interestingly, combined treatments of MGCD0103 and MC1568 or Tubastatin A resulted in cooperative (if not synergistic) induction of p21, but not CHK1 and γH2AX. These results strongly suggest that both classes I and II HDACs are involved in pancreatic cancer proliferation and survival, with class I HDACs playing predominant roles. Accordingly, treating pancreatic cancer with pan-HDACI (e.g., Panobinostat) will be more beneficial than class-or isoform-selective inhibitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1830. doi:1538-7445.AM2012-1830