Histone deacetylase (HDAC) encoding gene expression in pancreatic cancer cell lines and cell sensitivity to HDAC inhibitors

Abstract

Results: We have found that although a slight variation in the profiles of gene expression among cell lines could be evidenced, HDACs protein synthesis seem to be similar. Furthermore, the cells were equally sensitive to inhibition by Sirtinol whereas some variation in the IC 50 could be seen in the case of TSA. We also demonstrate that the drugs had the capacity to induce the death of cells by apoptosis.Methods: We have used four human pancreatic tumor cell lines and two-non related tumor cells, to evaluate the expression of HDAC encoding genes by RT-PCR and Western blot analysis. We also measured the effect of certain HDAC inhibitors (HDIs) on cell growth, cell cycle alteration, membrane phosphatidyl-serine exposure, DNA fragmentation and mitochondrial membrane potential loss.Conclusions: Taken together, our data support the notion that the level of cell sensitivity to the HDIs might be related to the level of expression of genes such as those encoding proteins playing a role in cell cycle checkpoints control but not HDAC per se.

Lysine deacetylases are produced in pancreatic beta cells and are differentially regulated by proinflammatory cytokines

“…In non-beta cells, information about the regulation of KDAC expression is limited. HDAC1 and HDAC6 were expressed at higher levels in pancreatic exocrine tumour cells than in non-transformed acinar cells [36]. The Hdac1 promoter lacks a TATA box consensus site, but has cis-binding sites for the transcription factors specificity protein-1 and nuclear transcription factor-Y.…”

Combined targeting of histone deacetylases and hedgehog signaling enhances cytoxicity in pancreatic cancer

“…Both Panc-1 and BxPC-3 were derived from primary pancreatic adenocarcinoma, 30,31 and they have been shown to express altered levels of HDACs, Hh signaling components, and HHIP. 4,17,32,33 To define the anti-proliferative effects of SAHA, SANT-1 and Gemcitabine on each cell line, dose response curves were obtained using the MTS assay (Suppl. Fig.…”

Epigenetic modulation and attacking the hedgehog pathway; potentially synergistic therapeutic targets for pancreatic cancer

“…6 Alterations in histone acetylases (HATs) and histone deacetylases (HDACs) are common in many cancer types including PC. [6][7][8] HDACs and HATs are recruited to specific gene promoters as part of the transcriptional machinery. An increase association of HDACs and/or decrease in HATs maintains surrounding chromatin in a compacted state, suppressing transcriptional activity.…”

“…Several HDAC inhibitors including SAHA and Vorinostat (Zolinza) are in clinical trials for solid tumors and these inhibitors have low toxicities and show specificity to tumor cells compared to normal tissues. 8 Preclinical studies indicate that HDAC inhibitors suppress the growth of PC cells lines and enhance apoptosis in gemcitabine-treated PC. 8 A potential clinical benefit of HDAC inhibitors in PC is supported by studies in other tumor types indicating that HDAC inhibitors synergize with chemotherapy to induce apoptosis.…”

“…8 Preclinical studies indicate that HDAC inhibitors suppress the growth of PC cells lines and enhance apoptosis in gemcitabine-treated PC. 8 A potential clinical benefit of HDAC inhibitors in PC is supported by studies in other tumor types indicating that HDAC inhibitors synergize with chemotherapy to induce apoptosis. 9 The end results of genetic and epigenetic alterations found in cancer cells are changes in cell signaling networks and altered gene expression.…”