E6E7 Regulates the HK2 Expression in Cervical Cancer Via GSK3β/FTO Signal.

Background: Cervical cancer is one of the most common cancers in women worldwide. Hexokinase 2 (HK2) is responsible for phosphorylating glucose into glucose-6-phosphate, which is required for tumorigenesis and metastasis. Methods: E6E7 and FTO were exogenously expressed, and their effects on HK2 mRNA and protein levels were detected by RT-qPCR and Western blot. Results: The exogenous expression of E6E7 in SiHa and C33A cells up-regulated the mRNA and protein levels of intracellular HK2, up-regulated the total m6A levels, changed the expression of m6A proteins and activated the GSK3B transcription. The expression levels of METTL3 and WTAP were enhanced, whereas the expression of FTO and ALKBH5 were decreased. In addition, FTO down-regulated the mRNA and protein levels of HK2. FTO overexpression partially inhibited the up-regulated expression of HK2 caused by E6E7. Furthermore, FTO overexpression increased the level of HK2 pre-mRNA in the nucleus and decreased the level of mature HK2 mRNA in the cytoplasm. We also found that GSK3B overexpression enhanced FTO ubiquitination and decreased FTO protein levels. Conclusion: This study found that E6E7 oncogene activates the transcription of GSK3B; GSK3B can promote the ubiquitination-proteasomal degradation of FTO and reduce the level of FTO protein; FTO inhibits the maturation and translation of HK2 mRNA by retaining HK2 pre-mRNA in the nucleus.