WTAP-mediated m6A modification of UBE2K drives the malignant progression of gastric cancer.

BACKGROUND

Gastric cancer (GC) remains one of the leading causes of cancer-related mortality worldwide. Ubiquitin-conjugating enzyme E2 K (UBE2K), defined as an E2, is involved in various cellular processes. N6-methyladenosine (m6A) is one of the most abundant subtypes of RNA modifications. However, the systematic role of UBE2K and whether UBE2K undergoes an m6A modification in GC remain unknown.

METHODS

The expression and prognosis of UBE2K in GC were analyzed through an online database. RT-qPCR, western blot and IHC were used to test the expression of UBE2K in GC tissues and cells. CCK-8, colony formation, transwell, wound healing and sphere formation assays were conducted to explore UBE2K's function in vitro. The subcutaneous mouse model was generated to validate UBE2K's role in tumorigenesis. RNA immunoprecipitation and RNA stability experiment were applied to investigate the molecular mechanism of UBE2K.

RESULTS

Higher expression of UBE2K was found in GC tissues and predicted worse prognosis. UBE2K knockdown suppressed the malignant progression of GC cells both in vitro and in vivo. Mechanistically, we found that UBE2K was regulated by m6A modification. WTAP was further revealed as the m6A writer of UBE2K to enhance UBE2K RNA stability. Finally, functional rescue experiments showed that silencing WTAP reversed the oncogenic effects of UBE2K overexpression on GC cells, whereas WTAP attenuated the suppression of GC cells induced by UBE2K knockdown.

CONCLUSION

Our findings indicate WTAP-mediated m6A modification upregulates UBE2K and the WTAP/UBE2K axis facilitates GC progression, suggesting a potential therapeutic target for GC treatment.