Investigation of the influence of BET proteins on NSD1 and their role in an epigenetic circuit influencing tumor viability in pancreatic cancer
Final Report Abstract
This project aimed at characterizing the effect of the histone methyltransferase NSD1 on PDAC cell viability and identifying possible downstream effectors. Furthermore, by employing inhibitors of BET bromodomain proteins, we sought to evaluate avenues of pharmacological inhibition of NSD1. These goals were achieved by using patient-derived cell lines and mouse models that closely recapitulate the biology of the disease. Knockdown of NSD1 in vitro was associated with a tremendous reduction of PDAC cell viability, which was also shown in orthotopic mouse models of immunodeficient mice. Furthermore, knockdown of NSD1 resulted in reduced H3K36 methylation, a marker of enhanced DNA elongation and transcription. Of note, single amino acid change of H3K36 resulted in reduced cell viability when comparing H3K36 to H3M36. Additionally, RNA-sequencing and gene ontology enrichment analysis of cells treated with NSD1-targeting shRNAs revealed inflammatory response as a potential group of genes mediating the effect of NSD1 on PDAC cells Not only did this project demonstrate the striking effects of NSD1 on PDAC cells in vitro, by using publicly available databases we also showed that decreased NSD1 expression is associated with improved 5-year survival in nodal positive PDAC. NSD1’s clinical importance is further underlined by the fact that sarcopenia, a marker of impaired survival, was reduced upon NSD1 knockdown in orthotopic mouse models of PDAC. In an effort to identify potential future clinical applications, PDAC cell lines were treated with BET bromodomain inhibitors. Treatment with BET inhibitors resulted in reduced NSD1 expression and reduced cell viability, indicating that BET inhibitors are worth evaluation in clinical trials of PDAC. Accordingly, this project demonstrates that NSD1 is an important factor in PDAC cell viability and acts by alteration of H3K36 methylation. Clinical studies are urgently needed to assess the effect of decreasing NSD1 expression via BET inhibition on patient outcomes in PDAC.
Publications
- The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship. Cancers (Basel) (09/2018)
Weniger M, Honselmann KC, Liss AS
(See online at https://doi.org/10.3390/cancers10090316) - Impact of Klebsiella Pneumoniae and Quinolones on Survival of Pancreatic Cancer. British Journal of Surgery (08/2020)
Weniger M, Hank T, Qadan M, Ciprani D, Michelakos T, Niess H, Heiliger C, Ilmer M, D’Haese JG, Ferrone CR, Warshaw AL, Lillemoe KD, Werner J, Liss AS, Fernandez CF
(See online at https://doi.org/10.1002/bjs.12003) - Preoperative cholangitis is an independent risk factor for mortality in patients after pancreatoduodenectomy for pancreatic cancer. American Journal of Surgery (08/2020)
Darnell P, Wang TJ, Lumish MA, Hernandez-Barco YG, Weniger M, Casey BW, Qadan M, Lillemoe KD, Ferrone CR, Fernandez CF, Krishnan K
(See online at https://doi.org/10.1016/j.amjsurg.2020.07.025) - Risk of malignancy in small pancreatic cysts decreases over time. Pancreatology (08/2020)
Ciprani D, Weniger, M, Qadan M, Hank, T, Horick, NK, Harrison, JM, Marchegiani, G, Andrianello, S, Pandharipande, PV, Ferrone, CR, Lillemoe, KD, Warshaw, AL, Bassi, C, Salvia, C, Fernandez CF
(See online at https://doi.org/10.1016/j.pan.2020.08.003)
