The feedback loop of EFTUD2/c-MYC impedes chemotherapeutic efficacy by enhancing EFTUD2 transcription and stabilizing c-MYC protein in colorectal cancer

Abstract Background Chemoresistance remains the primary cause of mortality in colorectal cancer (CRC). However, our understanding of the molecular basis underlying CRC chemoresistance is still limited. Elongation factor Tu GTP binding domain containing 2 (EFTUD2) has been implicated as a potential oncogenic factor in various cancer types, yet its specific role in regulating the sensitivity of CRC cells to chemotherapy remains unclear. Methods Public datasets analysis, along with our in-house sample validation were conducted to identify the expression of EFTUD2 in 5-FU-resistant CRC cells and patients. Experiments both in vitro including MTT assay, EdU cell proliferation assay and clone formation assay and in vivo were performed to elucidate the function of EFTUD2 in sensitivity of CRC cells to 5-FU treatment. The underlying mechanism was investigated through molecular docking, chromatin immunoprecipitation (Ch-IP), dual luciferase reporter gene assay, and co-immunoprecipitation (Co-IP). Results We observed a positive correlation between increased expression of EFTUD2 and resistance to the chemotherapeutic agent 5-FU in CRC cells, as well as with higher pathological grades and poor prognosis. Then we showed that down-regulation of EFTUD2 expression enhanced the sensitivity of CRC cells to 5-FU treatment. Mechanistically, we uncovered that EFTUD2 interacted with and stabilized the oncoprotein c-MYC by preventing ubiquitin-mediated proteasomal degradation. Intriguingly, we found that c-MYC, acting as a transcription factor, directly activated the transcriptional expression of EFTUD2 by binding to its promoter region. Furthermore, rescue experiments demonstrated that the impact of EFTUD2 on reducing the efficacy of 5-FU chemotherapy relied on c-MYC stabilization. Conclusion Our findings revealed a positive feedback loop involving the EFTUD2/c-MYC axis that hampers the chemotherapeutic sensitivity of CRC cells to 5-FU chemotherapy, thereby impairing treatment effectiveness and fostering CRC progression. This study highlights EFTUD2 as a promising therapeutic target for overcoming chemotherapy resistance in CRC.