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 m ⁶ A levels, changed the expression of m ⁶ A proteins and activated the GSK3β 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 GSK3β overexpression enhanced FTO ubiquitination and decreased FTO protein levels.
Conclusion: This study found that E6E7 oncogene activates the transcription of GSK3β; GSK3β 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.
Competing Interests: Declaration of competing interest The authors declare that they have no competing interests exist.
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