NSUN2 stimulates tumor progression via enhancing TIAM2 mRNA stability in pancreatic cancer

Abstract

NSUN2 is a nuclear RNA methyltransferase which catalyzes 5-methylcytosine (m5C), a posttranscriptional RNA modification. Aberrant m5C modification has been implicated in the development of multiple malignancies. However, its function in pancreatic cancer (PC) needs to be elucidated. Herein, we determined that NSUN2 was overexpressed in PC tissues and related to aggressive clinical features. Silence of NSUN2 by lentivirus weakened the capability of proliferation, migration and invasion of PC cells in vitro and inhibited the growth and metastasis of xenograft tumors in vivo. Contrarily, overexpression of NSUN2 stimulated PC growth and metastasis. Mechanistically, m5C-sequencing (m5C-seq) and RNA-sequencing (RNA-seq) were carried out to identify downstream targets of NSUN2 and results showed that loss of NSUN2 led to decreased m5C modification level concomitant with reduced TIAM2 mRNA expression. Further validation experiments proved that NSUN2 silence accelerated the decay of TIAM2 mRNA in a YBX1-dependent manner. Additionally, NSUN2 exerted its oncogenic function partially through enhancing TIAM2 transcription. More importantly, disruption of the NSUN2/TIAM2 axis repressed the malignant phenotype of PC cells through blocking epithelial-mesenchymal transition (EMT). Collectively, our study highlighted the critical function of NSUN2 in PC and provided novel mechanistic insights into NSUN2/TIAM2 axis as promising therapeutic targets against PC.

NSUN2 affects diabetic retinopathy progression by regulating MUC1 expression through RNA m5C methylation

“…Studies have shown that RNA m 5 C methylation can be directly recognized by readers (ALYREF or YBX1), affecting RNA processing and subsequent effects [ 30 ]. In our experiments, we found that the protein expression of ALYREF was elevated in the retinal tissues of DB/DB mice, whereas the change in the protein expression of YBX1 was not significant (Fig.…”

Metabolic Recoding of NSUN2‐Mediated m5C Modification Promotes the Progression of Colorectal Cancer via the NSUN2/YBX1/m5C‐ENO1 Positive Feedback Loop

“…[ 10 , 13 , 17 , 18 , 19 , 35 ] NSUN2 promotes the progression of multiple cancers via m 5 C modification of LIN28B , FABP5 , p57 Kip2 , PFAS , TIAM2 , and HDGF mRNA in esophageal squamous cell carcinoma, osteosarcoma, gastric cancer, retinoblastoma, pancreatic cancer and bladder cancer, respectively. [ 10 , 18 , 43 , 44 , 45 , 46 ] Correlation analysis further revealed that high levels of NSUN2 were significantly associated with clinical stage, lymph node metastasis, and distant metastasis. To verify these findings, colony formation, transwell invasion, and tumor sphere formation assays demonstrated that NSUN2 knockout significantly suppressed the proliferation, invasion, and cancer stemness of CRC cells.…”

Y-Box Binding Protein 1: Unraveling the Multifaceted Role in Cancer Development and Therapeutic Potential

“…Moreover, knockdown of YBX1 remarkedly inhibited cell invasion with downregulation of MMPs in vitro [110]. Silencing of YBX1 led to a reduction in T cell lymphoma invasion and metastasis mRNA stability, which mediated EMT migration and invasion in pancreatic cancer cells [132]. Abbreviations: SMURF2: SMAD-specific E3 ubiquitin protein ligase 2; CBX3: chromobox protein homolog 3; TIAM2: T cell lymphoma invasion and metastasis; MMPs: Matrix metalloproteinases; NUF2: cell division cycle-associated 1; PDXK: pyridoxal kinase.…”

“…Moreover, knockdown of YBX1 remarkedly inhibited cell invasion with downregulation of MMPs in vitro[110]. Silencing of YBX1 led to a reduction in T cell lymphoma invasion and metastasis mRNA stability, which mediated EMT migration and invasion in pancreatic cancer cells[132]. Abbreviations:…”