Int J Biol Sci 2022; 18(2):507-521. doi:10.7150/ijbs.67770 This issue

Research Paper

HPV E6/E7 promotes aerobic glycolysis in cervical cancer by regulating IGF2BP2 to stabilize m6A-MYC expression

Chenchen Hu1*, Tianyue Liu1*, Chenying Han1*, Yuxin Xuan2*, Dongbo Jiang1, Yuanjie Sun1, Xiyang Zhang1, Wenxin Zhang2, Yiming Xu2, Yang Liu1, Jingyu Pan1, Jing Wang1, Jiangjiang Fan1, Yinggang Che1, Yinan Huang1, Jiaxing Zhang1, Jiaqi Ding1, Shuya Yang1✉, Kun Yang1✉

1. Department of Immunology, Air Force Medical University (The Fourth Military Medical University), Xi'an, Shaanxi, 710032, China.
2. School of Basic Medicine, Air Force Medical University (The Fourth Military Medical University), Xi'an, Shaanxi, 710032, China.
*Co-first authors.

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Citation:
Hu C, Liu T, Han C, Xuan Y, Jiang D, Sun Y, Zhang X, Zhang W, Xu Y, Liu Y, Pan J, Wang J, Fan J, Che Y, Huang Y, Zhang J, Ding J, Yang S, Yang K. HPV E6/E7 promotes aerobic glycolysis in cervical cancer by regulating IGF2BP2 to stabilize m6A-MYC expression. Int J Biol Sci 2022; 18(2):507-521. doi:10.7150/ijbs.67770. Available from https://www.ijbs.com/v18p0507.htm

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Abstract

Graphic abstract

Enhanced aerobic glycolysis constitutes an additional source of energy for tumor proliferation and metastasis. Human papillomavirus (HPV) infection is the main cause of cervical cancer (CC); however, the associated molecular mechanisms remain poorly defined, as does the relationship between CC and aerobic glycolysis. To investigate whether HPV 16/18 E6/E7 can enhance aerobic glycolysis in CC, E6/E7 expression was knocked down in SiHa and HeLa cells using small interfering RNA (siRNA). Then, glucose uptake, lactate production, ATP levels, reactive oxygen species (ROS) content, extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were evaluated. RNA-seq was used to probe the molecular mechanism involved in E6/E7-driven aerobic glycolysis, and identified IGF2BP2 as a target of E6/E7. The regulatory effect of IGF2BP2 was confirmed by qRT-PCR, western blot, and RIP assay. The biological roles and mechanisms underlying how HPV E6/E7 and IGF2BP2 promote CC progression were confirmed in vitro and in vivo. Human CC tissue microarrays were used to analyze IGF2BP2 expression in CC. The knockdown of E6/E7 and IGF2BP2 attenuated the aerobic glycolytic capacity and growth of CC cells, while IGF2BP2 overexpression rescued this effect in vitro and in vivo. IGF2BP2 expression was higher in CC tissues than in adjacent tissues and was positively correlated with tumor stage. Mechanistically, E6/E7 proteins promoted aerobic glycolysis, proliferation, and metastasis in CC cells by regulating MYC mRNA m6A modifications through IGF2BP2. We found that E6/E7 promote CC by regulating MYC methylation sites via activating IGF2BP2 and established a link between E6/E7 and the promotion of aerobic glycolysis and CC progression. Blocking the HPV E6/E7-related metabolic pathway represents a potential strategy for the treatment of CC.

Keywords: HPV E6/E7, IGF2BP2, cervical cancer, aerobic glycolysis, m6A-MYC