NSD2 activates the E2F transcription factor 1/Y-box binding protein 2 axis to promote the malignant development of oral squamous cell carcinoma

Abstract

Objective: Nuclear receptor-binding SET domain protein 2 (NSD2) belongs to the SET histone methyltransferase family with potential oncogenic roles. This study aimed to probe the roles of NSD2 and its relevant molecules in oral squamous cell carcinoma (OSCC).

Methods: An OSCC-related GSE138206 dataset was analyzed to identify potential key genes implicated in OSCC development. NSD2 expression in OSCC tissues and cells was examined. NSD2 silencing was administrated in OSCC cells to examine its function in cell growth in vitro and in vivo. Downstream molecules mediated by NSD2 were predicted using bioinformatic tools. Rescue experiments of E2F transcription factor 1 (E2F1) and Y-box binding protein 2 (YBX2) were performed to validate their participation in NSD2-regulated events.

Results: NSD2 was highly expressed in OSCC tissues and cells, along with elevated expression of H3K36me2, a major target of NSD2-mediated methylation. NSD2 silencing significantly reduced proliferation, invasion and epithelial to mesenchymal transition of OSCC cells but induced cell apoptosis, and it reduced growth of xenograft tumors in nude mice. Downregulation of NSD2 led to transcriptional suppression of E2F1 by inhibiting H3K36me2 modification at the E2F1 promoter, while E2F1 transcriptionally activated YBX2. Either upregulation of E2F1 or YBX2 restored the malignant behaviors of OSCC cells suppressed by NSD2 silencing.

Conclusion: This work demonstrates that NSD2 plays an oncogenic role in OSCC by activating E2F1 and YBX2. Silencing of NSD2, E2F1 or YBX2 may help suppress the progression of OSCC.

Keywords: E2F transcription factor 1; NSD2; Oral squamous cell carcinoma; Y-box binding protein 2.