SHMT2 regulates esophageal cancer cell progression and immune Escape by mediating m6A modification of c-myc

Abstract

Background In recent years, the role of altered cellular metabolism in tumor progression has attracted widespread attention. Related metabolic enzymes have also been considered as potential cancer therapeutic targets. Serine hydroxymethyltransferase 2 (SHMT2) has been reported to be upregulated in several cancers and associated with poor prognosis. However, there are few studies of SHMT2 in esophageal cancer (EC), and the related functions and mechanisms also need to be further explored. Methods In this study, we first analyzed SHMT2 expression in EC by online database and clinical samples. Then, the biological functions of SHMT2 in EC were investigated by cell and animal experiments. The intracellular m6A methylation modification levels were also evaluated by MeRIP. Linked genes and mechanisms of SHMT2 were analyzed by bioinformatics and rescue experiments. Results We found that SHMT2 expression was abnormally upregulated in EC and associated with poor prognosis. Functionally, SHMT2 silencing suppressed c-myc expression in an m6A-dependent manner, thereby blocking the proliferation, migration, invasion and immune escape abilities of EC cells. Mechanistically, SHMT2 encouraged the accumulation of methyl donor SAM through a one-carbon metabolic network, thereby regulating the m6A modification and stability of c-myc mRNA in a METTL3/FTO/ALKBH5/IGF2BP2-dependent way. In vivo animal experiments also demonstrated that SHMT2 mediated MYC expression by m6A-methylation modification, thus boosting EC tumorigenesis. Conclusion In conclusion, our data illustrated that SHMT2 regulated malignant progression and immune escape of EC cell through c-myc m6A modification. These revealed mechanisms related to SHMT2 in EC and maybe offer promise for the development of new therapeutic approaches.

WTAP/IGF2BP3-mediated GBE1 expression accelerates the proliferation and enhances stemness in pancreatic cancer cells via upregulating c-Myc

“…As reported, c-Myc, acting as popular transcription factor, was abnormally expressed in multiple human cancers and involved in regulating cell behaviors including cell proliferation, stemness, apoptosis, angiogenesis and metabolism through regulating its target genes, thereby facilitating tumor malignant progression [ 45 – 47 ]. Zhe et al revealed that SHMT2 accelerating esophageal cancer development through enhancing c-Myc m6A modification and its expression [ 48 ]. LncRNA GLCC1 promoted colorectal cancer cell proliferation, glycolysis by enhancing c-Myc stabilization through suppressing c-Myc ubiquitination via binding to HSP90 [ 49 ].…”

The role of RNA methylation in tumor immunity and its potential in immunotherapy

“…Additionally, METTL3 is known to augment the immunosuppressive abilities of tumor-infiltrating myeloid cells [ 304 ]. In the context of EC, Serine hydroxymethyltransferase 2 (SHMT2) utilizes the METTL3/FTO/ALKBH5/IGF2BP2 pathway to mediate immune evasion by modifying c-myc through m6A [ 305 ]. These findings further indicate that IGF2BP3 plays a crucial role in the regulation of PD-1/PD-L1 degradation and impacts tumor immune responses.…”