Transcriptomic analysis of two human pancreatic cancer cell lines treated with the HDAC inhibitor romidepsin and/or the RNA helicase eIF4A inhibitor des-methyl pateamine A

Our study explores a small molecule combination that induces epigenetic reprogramming as a novel therapeutic strategy for pancreatic cancer. We have identified marked sensitivity of pancreatic cancer cells to the combination of a novel inhibitor of RNA helicase eIF4A, des-methyl pateamine A (DMPatA or MZ735), and a histone deacetylase (HDAC) inhibitor, romidepsin. A short-duration, low dose exposure to romidepsin treatment, when combined with DMPatA, triggers persistent global histone acetylation, transcriptional upregulation, replication inhibition, and augmented DNA damage. This combined effect induces a synergistic anti-proliferative response in pancreatic cancer cell lines. Global gene expression analysis was performed by RNA-seq in triplicate on 2 human pancreatic cancer cell lines (KLM and MIA PaCa-2) after treatment with either the HDAC inhibitor romidepsin (15 nM for a 6h treatment followed by 12h incubation with romidepsin-free medium), the RNA helicase eIF4A inhibitor DMPatA (2 nM, 18h), or a combination of both.