NSD2 mediates NF-κB and matrix metalloproteinases to drive hepatocellular carcinoma malignant progression

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality globally, with limited therapeutic options available for advanced stages. Elucidating the molecular drivers of hepatocarcinogenesis holds promise for the development of targeted therapeutic strategies. Nuclear receptor-binding SET domain-containing protein 2 (NSD2), a histone lysine methyltransferase, is now recognized as a critical modulator of tumor progression. The aim of this study was to investigate the role of NSD2 in HCC.

Messenger ribonucleic acid (mRNA) and protein levels were determined in 20 HCC patients, publicly available databases and HCC cell lines. The in vitro and in vivo phenotypic alterations upon NSD2 knockdown, such as cell proliferation, apoptosis, migration, invasion and xenograft tumor burden in male BALB/c nude mice, were assessed. The potential effects of NSD2 on nuclear factor kappa B (NF-κB) and matrix metalloproteinases (MMPs) were also analysed.

The findings revealed that NSD2 expression was markedly elevated in both HCC patients' samples and cell lines. Elevated NSD2 expression was closely linked to poor prognosis in HCC patients. Furthermore, our experimental findings highlighted the critical role of NSD2 in enhancing the proliferation, migration, and invasion of HCC cells, while simultaneously inhibiting apoptosis both in vitro and in vivo. Notably, our research indicated NF-κB and MMPs as key mediators in these critical processes.

In summary, NSD2 acts as a tumorigenic factor in the progression of HCC by activating the NF-κB and MMPs signalling pathways.