Abstract
The nuclear receptor-binding SET domain 3 (NSD3) catalyzes methylation of histone H3 at lysine 36 (H3K36), and promotes malignant transformation and progression of human cancer. Its expression, potential functions and underlying mechanisms in pancreatic cancer are studied. Bioinformatics studies and results from local human tissues show that NSD3 is upregulated in human pancreatic cancer tissues, which is correlated with poor overall survival. In primary and established pancreatic cancer cells, NSD3 silencing (by shRNAs) or CRISPR/Cas9-induced NSD3 knockout potently inhibited cell proliferation, migration and invasion, while provoking cell cycle arrest and apoptosis. Conversely, ectopic expression of NSD3-T1232A mutation significantly accelerated proliferation, migration, and invasion of pancreatic cancer cells. H3K36 dimethylation, expression of NSD3-dependent genes (Prkaa2, Myc, Irgm1, Adam12, and Notch3), and mTOR activation (S6K1 phosphorylation) were largely inhibited by NSD3 silencing or knockout. In vivo, intratumoral injection of adeno-associated virus (AAV)-packed NSD3 shRNA potently inhibited pancreatic cancer xenograft growth in nude mice. These results suggest that elevated NSD3 could be an important driver for the malignant progression of pancreatic cancer.
Highlights
Pancreatic cancer, mainly pancreatic ductal adenocarcinoma (PDAC), remains one of the most fatal malignancy in United States and around the world [1, 2]
We showed that shRNA-induced silencing of nuclear receptor-binding SET domain 3 (NSD3) significantly inhibited viability (CCK-8 OD) of PanCa-1 cells (Fig. 2C)
Cancer cells, derived from two other patients (PanCa-2 and PanCa-3), as well as established cell lines (PANC-1, MIA PaCa-2, and Bxpc-3), were tested. These cells were infected with shNSD3-S5 lentivirus, and stable cells established after puromycin selection. shNSD3-S5 resulted in over 85–90% reduction of NSD3 mRNA in the primary and established pancreatic cancer cells (Figs. 2H and S2A)
Summary
Pancreatic cancer, mainly pancreatic ductal adenocarcinoma (PDAC), remains one of the most fatal malignancy in United States and around the world [1, 2]. Cancer statistical analyses have predicted that deaths from pancreatic cancer would be second after lung cancer by 2030 [1, 2]. Gemcitabine, approved by FDA at 1997, is still the standard treatment of pancreatic cancer [3, 4]. Genetic driving factors, including KRAS and several others, have been identified in pancreatic cancer [5, 6]. Targeted therapies for pancreatic cancer are far from satisfactory [7, 8]. It is urgent to identify novel therapeutic targets and to explore effective treatments for pancreatic cancer [7, 8]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
