HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties

Abel, Ethan V.; Goto, Masashi; Magnuson, Brian; Abraham, Saji; Ramanathan, Nikita; Hotaling, Emily; Alaniz, Anthony A; Kumar‐Sinha, Chandan; Dziubinski, Michele; Urs, Sumithra; Wang, Lidong; Shi, Jiaqi; Waghray, Meghna; Ljungman, Mats; Crawford, Howard C.; Simeone, Diane M.

doi:10.7554/elife.33947

Cited by 66 publications

(55 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This result suggests that different GIACs indeed exhibit notable similarity in terms of their hyperactive MRTFs, which likely control similar downstream transcriptional programs. Some of these MRTFs are well-established GIAC specific oncogenes, such as CDX2 (34,35), GATA6 (10,36), KLF5 (10,11) and HNF1A (37), highlighting that ELMER is capable of identifying cancerspecific MRTFs.…”

Section: Identification Of Hyperactive Mrtfs In Giac Using Elmermentioning

confidence: 99%

Lineage-Specific Epigenomic and Genomic Activation of Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas

et al. 2020

View full text Add to dashboard Cite

Gastrointestinal adenocarcinomas (GIAC) of the tubular GI tract including esophagus, stomach, colon, and rectum comprise most GI cancers and share a spectrum of genomic features. However, the unified epigenomic changes specific to GIAC are poorly characterized. Using 907 GIAC samples from The Cancer Genome Atlas, we applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks and identify a list of functionally hyperactive master regulator (MR) TF shared across different GIAC. The top candidate HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. A complex interplay between the HNF4A promoter and three distal enhancer elements was coordinated by GIAC-specific MRTF including ELF3, GATA4, GATA6 and KLF5; HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptional activation of many downstream targets, including HNF1A and factors of Interleukin signaling, in a lineage-specific manner. Overall, our study provides new insights into the GIAC-specific gene regulatory networks and identifies potential therapeutic strategies against these common cancers. Statement of significance: Findings show that GIAC-specific master regulatory transcription factors control HNF4A via three distal enhancers to promote GIAC cell proliferation and survival. Research.

show abstract

Section: Identification Of Hyperactive Mrtfs In Giac Using Elmermentioning

confidence: 99%

Lineage-Specific Epigenomic and Genomic Activation of Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas

et al. 2020

View full text Add to dashboard Cite

show abstract

“…MIA PaCa-2 and PANC-1 are cell lines established from the resected pancreatic carcinoma and exhibited epithelial morphology [33,34]. HPDE is a non-transformed human pancreatic ductal epithelial cell line established from HPV E6/E7*-immortalization [35,36]. On the other hand, although not considered to be malignant, hPSC is a primary culture derived from a PDAC tumor resected from a patient who had undergone a Whipple procedure and therefore these cells exhibit classical hallmarks of activated stellate cells [37,38] associated with PDAC progression [39,40].…”

Section: Pmca4 Is the Major Pmca Isoform Expressed In Mia Paca-2 Pancmentioning

confidence: 99%

Plasma Membrane Ca2+ ATPase Isoform 4 (PMCA4) Has an Important Role in Numerous Hallmarks of Pancreatic Cancer

Sritangos

Alarcon

James

et al. 2020

Cancers

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is largely resistant to standard treatments leading to poor patient survival. The expression of plasma membrane calcium ATPase-4 (PMCA4) is reported to modulate key cancer hallmarks including cell migration, growth, and apoptotic resistance. Data-mining revealed that PMCA4 was over-expressed in pancreatic ductal adenocarcinoma (PDAC) tumors which correlated with poor patient survival. Western blot and RT-qPCR revealed that MIA PaCa-2 cells almost exclusively express PMCA4 making these a suitable cellular model of PDAC with poor patient survival. Knockdown of PMCA4 in MIA PaCa-2 cells (using siRNA) reduced cytosolic Ca2+ ([Ca2+]i) clearance, cell migration, and sensitized cells to apoptosis, without affecting cell growth. Knocking down PMCA4 had minimal effects on numerous metabolic parameters (as assessed using the Seahorse XF analyzer). In summary, this study provides the first evidence that PMCA4 is over-expressed in PDAC and plays a role in cell migration and apoptotic resistance in MIA PaCa-2 cells. This suggests that PMCA4 may offer an attractive novel therapeutic target in PDAC.

show abstract

“…This result suggests that different GIACs indeed exhibit notable similarity in terms of their hyperactive MRTFs, which likely control similar downstream transcriptional programs. Some of these MRTFs are well-established GIAC specific oncogenes, such as CDX2 [19, 20] , GATA6 [10, 21] , KLF5 [10, 11] and HNF1A [22], highlighting that ELMER is capable of identifying cancer-specific MRTFs.…”

Section: Resultsmentioning

confidence: 99%

Lineage-Specific Epigenomic and Genomic Activation of the Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas

Pan

Silva

Gull

et al. 2019

Preprint

View full text Add to dashboard Cite

AbstractBackgroundsGastrointestinal adenocarcinomas (GIACs) of the tubular GI tract including esophagus, stomach, colon and rectum comprise most GI cancers and share a spectrum of genomic features. However, the unified epigenomic changes specific to GIACs are less well-characterized.We applied mathematical algorithms to large-scale DNA methylome and transcriptome profiles to reconstruct transcription factor (TF) networks using 907 GIAC samples from The Cancer Genome Atlas (TCGA). Complementary epigenomic technologies were performed to investigate HNF4A activation, including Circularized Chromosome Conformation Capture (4C), Chromatin immunoprecipitation (ChIP) sequencing, Whole Genome Bisulfite Sequencing (WGBS), and Assay for Transposase-Accessible Chromatin (ATAC) sequencing. In vitro and in vivo cellular phenotypical assays were conducted to study HNF4A functions.ResultsWe identified a list of functionally hyperactive master regulator (MR)TFs shared across different GIACs. As the top candidate, HNF4A exhibited prominent genomic and epigenomic activation in a GIAC-specific manner. We further characterized a complex interplay between HNF4A promoter and three distal enhancer elements, which was coordinated by GIAC-specific MRTFs including ELF3, GATA4, GATA6 and KLF5. HNF4A also self-regulated its own promoter and enhancers. Functionally, HNF4A promoted cancer proliferation and survival by transcriptionally activating many downstream targets including HNF1A and factors of Interleukin signaling in a lineage-specific manner.ConclusionWe use a large cohort of patient samples and an unbiased mathematical approach to highlight lineage-specific oncogenic MRTFs, which provide new insights into the GIAC-specific gene regulatory networks, and identify potential therapeutic strategies against these common cancers.

show abstract

HNF1A is a novel oncogene that regulates human pancreatic cancer stem cell properties

Cited by 66 publications

References 77 publications

Lineage-Specific Epigenomic and Genomic Activation of Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas

Lineage-Specific Epigenomic and Genomic Activation of Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas

Plasma Membrane Ca2+ ATPase Isoform 4 (PMCA4) Has an Important Role in Numerous Hallmarks of Pancreatic Cancer

Lineage-Specific Epigenomic and Genomic Activation of the Oncogene HNF4A Promotes Gastrointestinal Adenocarcinomas

Contact Info

Product

Resources

About