GSE108149
HNF1A is a Novel Oncogene and Central Regulator of Pancreatic Cancer Stem Cells [Bru-seq]
The biological properties of pancreatic cancer stem cells (PCSCs) remain incompletely defined and the central regulators are unknown. By bioinformatic analysis of a PCSC-enriched gene signature, we identified the transcription factor HNF1A as a putative central regulator of PCSC function. Levels of HNF1A and its target genes were found to be elevated in PCSCs and tumorspheres, and depletion of HNF1A resulted in growth inhibition, apoptosis, impaired tumorsphere formation, PCSC depletion, and downregulation of OCT4 expression. Conversely, HNF1A overexpression increased PCSC numbers and tumorsphere formation in pancreatic cancer cells and drove PDA cell growth. Importantly, depletion of HNF1A in primary tumor xenografts impaired tumor growth and depleted PCSCs in vivo. Finally, we established an HNF1A-dependent gene signature in PDA cells that significantly correlated with reduced survivability in patients. These findings identify HNF1A as a central transcriptional regulator of the PCSC state and novel oncogene in pancreatic ductal adenocarcinoma. Overall design: Nascent RNA expression following HNF1A RNAi in the human pancreatic cancer cell lines NY8 and NY15.  This study consists of 12 Bru-seq samples. 2 sets of libraries (biological replicates) were generated from shRNA-treated cells from each cell line, including a control shRNA (LacZ sh) and two different HNF1A-targeting shRNAs (HNF1A sh1 and sh2).