Purpose:
NSD3 (WHSC1L1) is a protein lysine methyltransferase that is recurrently amplified (8p11.23) in several cancer types, and its upregulation is involved in tumor cell proliferation, metastasis, and epithelial-mesenchymal transition (EMT). We aimed to evaluate its potential function as an oncogenic force in colorectal cancer (CRC), and to elucidate relevant mechanisms of its oncogenic activity.
Materials and methods:
NSD3 levels were analyzed in human CRC and adjacent normal tissues or cells by Western blot analysis and RT-qPCR. Expression levels of the proteins were detected by Western blot analysis and RT-qPCR.
Results:
NSD3 was significantly upregulated in both CRC tissues and cell lines. Knockdown of NSD3 expression resulted in significant decreases in CRC cell proliferation, migration, and EMT process marker proteins vimentin, simultaneously reducing E-cadherin and N-cadherin expression. The opposite results were observed when NSD3 was overexpressed. Additionally, overexpressing of NSD3 dramatically activated the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and enhanced actin-capping protein (CAPG) expression. Furthermore, the proliferation and migration abilities evidently facilitated by pcDNA3.1(+) expression vector containing full-length CDS of NSD3 (pcDNA3.1(+)-NSD3, or NSD3) were partially decreased after incubation with ERK1/2 signaling pathway inhibitor (PD98059) and/or specific siRNA against CAPG (siCAPG) in SW480 and HT-29 CRC cells.
Conclusion:
NSD3 overexpression stimulated CRC cell proliferation and migration through targeting the ERK1/2 signaling pathway and downstream CAPG. Thus, NSD3 could serve as a promising target for anticancer drug development for patients with CRC.
Background: Emerging research indicates that CXXC finger protein 5 (CXXC5) is involved in the development of various cancers. Besides, KN motif and ankyrin repeat domains 1 (KANK1) was proved as a tumor suppressor in multiple cancers. Our study aimed to illustrate the functional role and mechanism of CXXC5 and KANK1 in gastric cancer (GC) pathogenesis. Methods: The tissues of 55 GC patients and six GC cell lines were used to investigate CXXC5 and KANK1 expression using RT-qPCR. Western blot assay was conducted to measure the protein levels of CXXC5, KANK1, epithelial-mesenchymal transformation (EMT) proteins (Vimentin, E-cadherin) and Wnt signaling proteins (β-catenin, Axin2). The correlation between KANK1 and CXXC5 was estimated by Pearson's correlation analysis. The results of Transwell assays showed the migration and invasion abilities of GC cells, while the apoptosis rate was detected by flow cytometry. Results: The expressions of CXXC5 and KANK1 were both decreased in GC tissues and cells, compared with the normal ones (P < 0.01). Overexpressing CXXC5 significantly induced apoptosis (P < 0.05) and inhibited EMT, migration (P < 0.05) and invasion (P < 0.01) in GC cells. Wnt/β-catenin/Axin2 signaling was suppressed by CXXC5 overexpression, and activating Wnt/β-catenin/Axin2 signaling reversed the effects of CXXC5. The expression of KANK1 was found to be positively correlated with CXXC5 (r 2 = 0.4024). KANK1 presented similar effects with CXXC5 on GC cells; however, silencing CXXC5 or activating Wnt/β-catenin/Axin2 signaling antagonized the effects of KANK1 overexpression on EMT and apoptosis in GC (P < 0.05). Conclusion: Our study suggested that CXXC5 was downregulated in GC and participated in EMT and apoptosis regulations via the Wnt/β-catenin/Axin2 pathway. Besides, the decreased expression of CXXC5 in GC was caused by KANK1 dysregulation.
These findings suggest that fibrocystin/primary cilia-dependent mechanisms may play a role in the regulation of pancreatic ductal structure and fluid secretion.
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