An integrated transcriptome and epigenome analysis identifies a novel candidate gene for pancreatic cancer

Abstract

BackgroundPancreatic cancer is a highly lethal cancer with limited diagnostic and therapeutic modalities.MethodsTo begin to explore the genomic landscape of pancreatic cancer, we used massively parallel sequencing to catalog and compare transcribed regions and potential regulatory elements in two human cell lines derived from normal and cancerous pancreas.ResultsBy RNA-sequencing, we identified 2,146 differentially expressed genes in these cell lines that were enriched in cancer related pathways and biological processes that include cell adhesion, growth factor and receptor activity, signaling, transcription and differentiation. Our high throughput Chromatin immunoprecipitation (ChIP) sequence analysis furthermore identified over 100,000 regions enriched in epigenetic marks, showing either positive (H3K4me1, H3K4me3, RNA Pol II) or negative (H3K27me3) correlation with gene expression. Notably, an overall enrichment of RNA Pol II binding and depletion of H3K27me3 binding were seen in the cancer derived cell line as compared to the normal derived cell line. By selecting genes for further assessment based on this difference, we confirmed enhanced expression of aldehyde dehydrogenase 1A3 (ALDH1A3) in two larger sets of pancreatic cancer cell lines and in tumor tissues as compared to normal derived tissues.ConclusionsAs aldehyde dehydrogenase (ALDH) activity is a key feature of cancer stem cells, our results indicate that a member of the ALDH superfamily, ALDH1A3, may be upregulated in pancreatic cancer, where it could mark pancreatic cancer stem cells.

Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues

“…This enrichment replicated in ChIP-seq data sets generated by our laboratory for H3K4me1 and H3K4me3 in tumour (PANC-1) and normal-derived (hTERT-HPNE) pancreatic cell lines20 with similar magnitudes (table 3B). Among three TFs with ChIP-seq data available for PANC-1 cells in ENCODE, the greatest enrichment for cis -eQTLs was observed for paired amphipathic helix protein Sin3a (SIN3A), a transcriptional regulator and epigenetic modifier most frequently associated with gene silencing 26.…”

ALDH1A3, a metabolic target for cancer diagnosis and therapy

“…Pancreatic cancer 58,59 Cancer tissue 58,59 Normal tissue 58,59 Ovarian cancer 60 Borderline ovarian tumor, invasive cancer 60 Normal tissue 60 Uterine cancer 60 Endometrial carcinoma, mucoid carcinoma 60 Clear cell carcinoma, serous carcinoma 60 Bladder cancer 68 Normal tissue 68 NMIBC 68 Glioma 69 High-grade glioma (HGG) 69 Low-grade glioma (LGG), normal tissue 69 Mes-GSCs 69 PN-GSCs 69 GBM with good prognosis 69 GBM with poor prognosis 69 Breast cancer 26,57,65 Cancer tissue 57 Normal tissue 57 Poorly differentiated 26 Well differentiated 26 Metastatic patients 26 Non-metastatic patients 26 expression. The inhibition of c-MET expression using siRNA or the inhibition of c-MET activity in AsPC-1 pancreatic cancer cells using SU11273 significantly decreased ALDH1A3 expression and Aldefluor activity.…”

Aldehyde Dehydrogenase 1B1 as a Modulator of Pancreatic Adenocarcinoma

“…In addition, ALDH1A1 protein expression is associated with reduced survival 21,23 and ALDH1A3 gene expression has been identified to be elevated in pancreatic cancer. 30 Although ALDH1A1 and ALDH1A3 have been proposed to be major contributors to ALDH enzymatic activity and cancer development, we have recently determined that the ALDH1B1 isozyme was upregulated in colorectal cancer. 24 In the present study, we demonstrated that ALDH1B1 protein expression was upregulated in pancreatic cancer.…”