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Downregulation of NSD3 (WHSC1L1) inhibits cell proliferation and migration via ERK1/2 deactivation and decreasing CAPG expression in colorectal cancer cells

Authors Yi L, Yi L, Liu Q, Li C

Received 22 October 2018

Accepted for publication 14 March 2019

Published 21 May 2019 Volume 2019:12 Pages 3933—3943

DOI https://doi.org/10.2147/OTT.S191732

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Ms Justinn Cochran

Peer reviewer comments 2

Editor who approved publication: Dr Federico Perche


Lanjuan Yi,1 Lanjie Yi,2 Qing Liu,3 Chen Li4

1Department of gastroenterology, Yantai Shan Hospital, Yantai, Shandong 264001, People’s Republic of China; 2Research Office of Clinical literature, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, People’s Republic of China; 3Department of Nosocomial Infection Control, Xuzhou Hospital of Traditional Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 310015, People’s Republic of China; 4Department of Gastroenterology, Xuzhou Chinese Medicine Hospital Affiliated to Nanjing University of Chinese Medicine, Xuzhou, Jiangsu 310015, People’s Republic of China

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.

Keywords: colorectal cancer, histone methyltransferase NSD3, extracellular signal-regulated kinase 1/2, actin-capping protein (CAPG)

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