Cancer-associated fibroblast-derived exosomal NSUN2-mediated m5C methylation promotes esophageal squamous cell carcinoma progression by NSUN2/YBX1/m5C-GOLPH3/SEC13 axis

Esophageal squamous cell carcinoma (ESCC) is a common malignancy in the developing world with significant mortality and poor outcomes. Cancer-associated fibroblasts (CAFs) are central components of tumor microenvironment and can affect tumor cell growth, metabolism and metastasis through releasing cytokines and growth factors. NSUN2 is an RNA m5C methyltransferases that catalyzes m5C modification. However whether CAF-derived NSUN2 affects ESCC progression by m5C-depdendent mechanism remains unclear. Here, we found that CAFs promoted the proliferation, metastasis and glycolysis of ESCC cells. Moreover, CAFs released NSUN2 into ESCC cells via exosome, and then induced m5C methylation. NSUN2 was highly expressed in ESCC tissues and cells. The introduction of exosomal NSUN2-decreased CAFs suppressed the proliferation, metastasis and glycolysis of ESCC cells. In addition, NSUN2 mediated GOLPH3 m5C methylation, and stabilized GOLPH3 mRNA in a YBX1-dependent mechanism. Overexpression of GOLPH3 could reverse the anticancer effects of exosomal NSUN2-decreased CAFs on ESCC cells. Moreover, GOLPH3 interacted with SEC13 protein. The suppression of ESCC cell proliferation, metastasis and glycolysis caused by GOLPH3 silencing was rescued by SEC13 overexpression. Besides that, exosomal NSUN2-decreased CAFs regulated SEC13 expression via GOLPH3. Further in vivo assays showed that exosomal NSUN2-decreased CAFs suppress ESCC growth and metastasis in vivo .