NSUN2 promotes colorectal cancer progression and increases lapatinib sensitivity by enhancing CUL4B/ErbB-STAT3 signalling in a non-m5C manner

Abstract

NSUN2, a major methyltransferase that catalyzes m5C methylation in eukaryotes, is known to be implicated in the development of multiple cancers. However, its role in colorectal cancer (CRC) and the related molecular mechanisms have yet to be sufficiently determined. Here, we conducted an analysis of public database (722 CRC patients) and two distinct cohorts from our centre (1559 CRC patients), which revealed that NSUN2 is upregulated in CRC and correlates with unfavourable prognosis. Our analyses also showed that NSUN2 promotes the proliferation and metastasis capabilities of CRC cells. Intriguingly, NSUN2 was found to promote CRC via an m5C-independent mechanism, which has not been previously reported. Overexpression of both wild-type and m5C enzymatic-dead mutant NSUN2 upregulated and activated the ErbB-STAT3 signalling pathway. We also found that both wild-type and the m5C enzymatic-dead mutant NSUN2 closely interacted with CUL4B. Silencing of CUL4B effectively inhibited the m5C-independent function of NSUN2. Moreover, overexpression of NSUN2 enhanced the sensitivity of CRC cells to lapatinib. Taken together, our findings revealed a novel m5C-independent mechanism for NSUN2 in the malignancy and lapatinib sensitivity of CRC via activation of the CUL4B/ErbB-STAT3 pathway, which provides a potential therapeutic strategy for patients with CRC.

Keywords

Colorectal cancer / ErbB-STAT3 signalling pathway / m5C-independent function / NSUN2

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.