# NSUN2 promoted tumor growth and metastatic via m5C-regulation of YAP through ALYREF/YBX1 axis in NSCLC

## TL;DR

This paper shows how NSUN2 promotes lung cancer growth and spread by modifying RNA with m5C, which stabilizes YAP protein through interactions with ALYREF and YBX1.

## Contribution

The study reveals a novel m5C-dependent mechanism involving NSUN2, ALYREF, and YBX1 that regulates YAP expression to drive NSCLC progression.

## Key findings

- NSUN2 increases YAP mRNA stability and translation via m5C modification.
- ALYREF and YBX1 interact with YAP mRNA in an m5C-dependent manner to enhance YAP expression.
- NSUN2 forms a positive feedback loop with YAP-TEAD2, promoting tumor growth and metastasis in NSCLC.

## Abstract

NSUN2-dependent RNA m5C methylation is essential for RNA stability, cellular metabolism, and intracellular transport. Aberrant YAP expression is closely associated with tumorigenesis and progression in human cancers. However, the molecular mechanism by which m⁵C regulates the growth and metastasis of NSCLC through modulating YAP expression remains incompletely understood. Our results demonstrate that YAP and NSUN2 play analogous roles in regulating NSCLC cell growth, migration, invasion, and EMT. NSUN2 increased m5C modification of YAP mRNA. ALYREF and YBX1 combined and then interacted with YAP mRNA in an m5C-dependent manner to increase YAP stability and translation. Importantly, NSUN2, ALYREF and YBX1 bind to each other and affected their interaction with YAP mRNA. Mechanistically, NSUN2 first initiates the m5C within YAP mRNA and then ALYREF recognizes m5C modification on YAP mRNA, YBX1 was more likely to bind to the transitive m5C from ALYREF and then promoted YAP mRNA stability through impeding the combination between AGO2 and YAP mRNA whereby increasing the expression of YAP with interaction with eIF3a and thus excessive cell growth and metastasis via regulation of YAP’s target genes of CTGF, Cyr61 MMP2, MMP9 in NSCLC. Moreover, NSUN2 is transcriptionally activated by the YAP-TEAD2 complex, forming a positive feedback loop that promotes tumor growth and metastasis, a process effectively suppressed by m5C inhibitors both in vivo and in vitro. Furthermore, our presented findings suggest that NSUN2 promotes tumor growth and metastasis by increasing ALYREF/YBX1-mediated YAP expression in NSCLC and effective inhibition of m5C modification might provide a potential treatment strategy for NSCLC.