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Elevated expression of nuclear receptor-binding SET domain 3 promotes pancreatic cancer cell growth.

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.

SUBMITTER: Sun Y

PROVIDER: S-EPMC8494902 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Elevated expression of nuclear receptor-binding SET domain 3 promotes pancreatic cancer cell growth.

Sun Yihui Y Xie Jiaming J Cai Shang S Wang Qian Q Feng Zhenyu Z Li Yecheng Y Lu Jing-Jing JJ Chen Wei W Ye Zhenyu Z

Cell death & disease 20211006 10

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, ...[more]

PMID: 34615858

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Project description:BackgroundMembers of the nuclear receptor-binding SET domain (NSD) family of histone H3 lysine 36 methyltransferases comprise NSD1, NSD2 (MMSET/WHSC1), and NSD3 (Wolf-Hirschhorn syndrome candidate 1-like 1, WHSC1L1). While the expression of NSD genes is essential to normal biological processes and cancer, knowledge of their expression levels to prognosticate in cancer remains unclear.MethodsWe analyzed the expression patterns for NSD family genes across multiple cancer types and examined their association with clinical features and patient survival profiles. Next, we explored the association between NSD3 expression and described features of the tumor microenvironment (TME) in PAAD, a severe type of pancreatic cancer. In particular, we correlated promoter methylation levels for NSD3 with patient outcomes in PAAD. Finally, we explored the putative oncogenic roles for NSD3 using a series of experiments with pancreatic cancer cells.ResultsWe report that the expression of NSD family members is correlated with clinical prognosis across multiple types of cancers. Also, we demonstrate that NSD3 variants are most prevalent among NSD genes across cancers we analyzed. Notably, when compared with NSD1 and NSD2, we find that NSD3 is prominently expressed, and its expression is significantly linked with clinical outcome in pancreatic cancer. Furthermore, NSD3 is frequently amplified, exhibits low promoter methylation, and is correlated with immune cell infiltration and enhanced proliferation of pancreatic cancer. Finally, we demonstrate that knockdown of NSD3 alters H3K36me2 methylation, downstream gene expression and EGFR/ERK signaling in pancreatic cancer cells.ConclusionsWe find that expression levels, the presence of genetic variants of NSD family genes, as well as their promoter methylation are correlated with clinical outcomes in cancer, including pancreatic cancer. Our in vitro experiments suggest that NSD3 may be relevant to gene expression regulation and growth factor signaling in pancreatic cancer.

Project description:The identification of prognostic tumor biomarkers that also would have potential as therapeutic targets, particularly in patients with early stage disease, has been a long sought-after goal in the management and treatment of lung cancer. The nuclear receptor (NR) superfamily, which is composed of 48 transcription factors that govern complex physiologic and pathophysiologic processes, could represent a unique subset of these biomarkers. In fact, many members of this family are the targets of already identified selective receptor modulators, providing a direct link between individual tumor NR quantitation and selection of therapy. The goal of this study, which begins this overall strategy, was to investigate the association between mRNA expression of the NR superfamily and the clinical outcome for patients with lung cancer, and to test whether a tumor NR gene signature provided useful information (over available clinical data) for patients with lung cancer.Using quantitative real-time PCR to study NR expression in 30 microdissected non-small-cell lung cancers (NSCLCs) and their pair-matched normal lung epithelium, we found great variability in NR expression among patients' tumor and non-involved lung epithelium, found a strong association between NR expression and clinical outcome, and identified an NR gene signature from both normal and tumor tissues that predicted patient survival time and disease recurrence. The NR signature derived from the initial 30 NSCLC samples was validated in two independent microarray datasets derived from 442 and 117 resected lung adenocarcinomas. The NR gene signature was also validated in 130 squamous cell carcinomas. The prognostic signature in tumors could be distilled to expression of two NRs, short heterodimer partner and progesterone receptor, as single gene predictors of NSCLC patient survival time, including for patients with stage I disease. Of equal interest, the studies of microdissected histologically normal epithelium and matched tumors identified expression in normal (but not tumor) epithelium of NGFIB3 and mineralocorticoid receptor as single gene predictors of good prognosis.NR expression is strongly associated with clinical outcomes for patients with lung cancer, and this expression profile provides a unique prognostic signature for lung cancer patient survival time, particularly for those with early stage disease. This study highlights the potential use of NRs as a rational set of therapeutically tractable genes as theragnostic biomarkers, and specifically identifies short heterodimer partner and progesterone receptor in tumors, and NGFIB3 and MR in non-neoplastic lung epithelium, for future detailed translational study in lung cancer. Please see later in the article for the Editors' Summary.

Project description:Hepatoma-derived growth factor (HDGF) is a nuclear protein with both mitogenic and angiogenic activity that is highly expressed in the developing heart and vasculature. To date, the mechanism underlying the function of HDGF is unknown. Oligonucleotide microarray analysis was used to gain insights into HDGF function. Adenoviral expression of HDGF significantly (> or =2-fold) downregulated a large group (66) of genes, and increased expression of a relatively small number of genes (9). Two groups of target genes that are involved in cardiovascular development and transcriptional regulation, including the skeletal/cardiac muscle specific SET and MYND domain containing 1 (SMYD1) gene, were validated by real time PCR. This suggested that HDGF could function as a transcriptional repressor. In a one-hybrid system, GBD-HDGF significantly repressed reporter gene activity in a dose-dependent manner. This demonstrated that HDGF has transcriptional repressive activity. Moreover, in G-7 myoblast cells, over-expression of a GFP-HDGF fusion specifically downregulated SMYD1 mRNA expression and the activity of the human SMYD1 promoter. HDGF repressed SMYD1 gene transcription through interaction with a transcriptional corepressor C-terminal binding protein (CtBP). Over-expression of CtBP potentiated the trans-repressive activity of HDGF; on the other hand, knocking down CtBP attenuated the trans-repressive effect of HDGF. HDGF binds CtBP through a non-canonical binding motif (PKDLF) within the PWWP domain, as mutation of DL to AS abolished HDGF and CtBP interaction, and diminished the trans-repressive effect of HDGF without affecting DNA binding. Finally, fluorescent microscopy showed that HDGF induced the nuclear accumulation of CtBP, suggesting that HDGF forms a transcriptional complex with CtBP. Taken together, our data demonstrate that HDGF functions as a transcriptional repressor of the SMYD1 gene through interaction with the transcriptional corepressor CtBP. Because of moderate conservation of the CtBP binding motif in HDGF family members, trans-repressive activity mediated by CtBP may be a common function among HDGF proteins.

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Elevated expression of nuclear receptor-binding SET domain 3 promotes pancreatic cancer cell growth.

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Elevated expression of nuclear receptor-binding SET domain 3 promotes pancreatic cancer cell growth.

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