NSD2 activates the E2F transcription factor 1/Y-box binding protein 2 axis to promote the malignant development of oral squamous cell carcinoma
Introduction
Squamous cell carcinoma (SCC) is the major malignancy of oral mucosa and lip, and oral squamous cell carcinoma (OSCC) makes up 95% of all head and neck cancer and represents one of the major causes of cancer-related death in the world (Choi and Myers, 2008, Panarese et al., 2019, Sharma et al., 2018). The occurrence of OSCC is particularly high in Asia owing to the bad lifestyle habits, such as chewing of betel quid, smoking, drinking, infection and poor oral hygiene (Yu-Duan et al., 2013). Since the tumor formation, the tumor cells may break off from the original sites and migrate to other sites of the body (Matsuura et al., 2018). The metastasis in the setting of late diagnosis is a major cause of death (Irani, 2016, Noguti et al., 2012). Although there are effective therapeutic options by far, such as surgery, radiotherapy and adjuvant chemotherapy, the 5-year survival rate only moderately improved from 63% to 65% during the past decades (He et al., 2019, Zou et al., 2019). It is urgent to identify key molecules implicated in the progression of OSCC, which may help develop novel treating strategies for this malignancy.
Advanced bioinformatic tools have offered great convenience in the quick and concrete identification of key genes implicated in the pathogenesis of diseases (Huang, Wu, Zheng, Shao, & Lv, 2019). In this study, using an OSCC-related GSE138206 dataset from GEO (https://www.ncbi.nlm.nih.gov/geo/), we identified nuclear receptor-binding SET domain protein 2 (NSD2) as a candidate molecule leading to cancerigenesis of OSCC. NSD2 is a member of the SET histone methyltransferase family (Tanaka et al., 2020). The NSD2 protein methylates specific histone sites, including H3 lysine 36 (H3K36me2), an active mark leading to transcriptional activation (Li et al., 2009). NSD2 has reportedly been correlated with malignant development of several human cancers via activating the oncogenic signaling pathways (Garcia-Carpizo et al., 2016, Yang et al., 2012, Zhu et al., 2019) through the epigenetic regulations. Damaging mutation of NSD2 has been correlated with favorable prognosis of laryngeal cancer (Peri et al., 2017), indicating its potential correlation with other SCCs of head and neck (SCCHN), including OSCC. But the exact role of NSD2 in OSCC needs further investigation.
The bioinformatic analyses of this study predicted E2F transcription factor 1 (E2F1) as a target of NSD2, and Y-box binding protein 2 (YBX2) a target of E2F1. E2F1 is a transcriptional activator of the E2F family of transcription factors in higher eukaryotes (Sozzani et al., 2006, pp. 106). It is frequently involved in cancer progression through regulating cell cycle progression as well as epithelial to mesenchymal transition (EMT) and metastatic events (Alla et al., 2010, Gaubatz et al., 2000, Marquardt et al., 2018, Swiatnicki and Andrechek, 2021). As far as YBX2, it is a member of the YBX family of RNA binding proteins correlated with DNA repair, transcription and translation (Kohno, Izumi, Uchiumi, Ashizuka, & Kuwano, 2003). YBX2 has been demonstrated to be correlated with the properties of germ cells and cancer cells (Suzuki et al., 2021). Therefore, there might be a NSD2/E2F1/YBX2 axis involved in the progression of OSCC. This study aimed to validate the interactions between NSD2, E2F1 and YBX2 and their functions in the growth of OSCC cells in vitro and in vivo.
Section snippets
Sample collection
OSCC tissues and the paired normal tissues were harvested from 60 patients diagnosed and treated at Affiliated Hospital of Beihua University from January 2019 to May 2020. OSCC in patients was diagnosed by three pathologists. Fresh tissues were instantly frozen in liquid nitrogen after surgery and stored at − 80 ℃ until further use. All patients did not receive any other therapies, such as radio- or chemo-therapy before surgical resection. This research was ratified by the Ethics Committee of
NSD2 is expressed at high levels in OSCC tissues and cells
A GSE138206 dataset which contains complete data of gene expression data in OSCC tumor tissues and the adjacent tumors was downloaded from GEO, whereas many other GEO datasets do not contain complete data in their Series Matrix File (s) were not used for analysis. A single dataset for differential gene expression has also been applied in several recent publications (Liu et al., 2021, Maimaiti et al., 2022, Wu et al., 2022). In this work, differentially expressed mRNAs between OSCC and normal
Discussion
Owing to the lack of early signs, most of the OSCC cases are not diagnosed until later stages (Imani et al., 2018). The 5-year survival rate of patients with OSCC, especially with metastatic disease, is still unfavorable regardless of a large number of basic and clinical studies have been launched (Jie, Bai, & Li, 2018). Anyway, identifying effective causative factors of this disease remains a key issue for the development of novel therapeutic options. This work reports that the histone
Conclusion
In conclusion, this paper demonstrates that NSD2 is upregulated in OSCC and it upregulates E2F1 through H3K36me2 modification and leads to resultant activation of YBX2, which promotes growth, invasion and EMT whereas reduces apoptosis of OSCC cells. The findings may provide new ideas in the management of OSCC. The expression levels of NSD2, E2F1 and YBX2 should be further explored as novel clinical metrics for the stratification and prognostication of patients with OSCC.
Funding
This work was supported by the Science and Technology Research Project of Jilin Provincial Department of Education (No. JJKH20200073KJ).
CRediT authorship contribution statement
Lili Zhang: Conceptualization, Methodology, Experimental studies, Software, Manuscript preparation. Lili Zhang and Guangyao Hu: Data curation, Statistical analysis, Visualization, Writing – review & editing, Validation. All authors read and approved the final manuscript.
Declaration of Competing Interest
The authors report no declarations of interest.
Acknowledgements
We thanks to the Science and Technology Research Project of Jilin Provincial Department of Education (No. JJKH20200073KJ) for the funding support.
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