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

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.

• Authors: Chenchen Hu, Tianyue Liu, Chenying Han, Yuxin Xuan, Dongbo Jiang, Yuanjie Sun, Xiyang Zhang, Wenxin Zhang, Yiming Xu, Yang Liu, Jingyu Pan, Jing Wang, Jiangjiang Fan, Yinggang Che, Yinan Huang, Jiaxing Zhang, Jiaqi Ding, Shuya Yang, Kun Yang
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 18 Issue 2 Pg. 507-521 ( 2022) ISSN: 1449-2288 [Electronic] Australia
• PMID: 35002506 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The author(s).

Chemical References

• DNA-Binding Proteins
• E6 protein, Human papillomavirus type 16
• E6 protein, Human papillomavirus type 18
• IGF2BP2 protein, human
• Oncogene Proteins, Viral
• Papillomavirus E7 Proteins
• Proto-Oncogene Proteins c-myc
• RNA, Messenger
• RNA, Small Interfering
• RNA-Binding Proteins
• Repressor Proteins
• oncogene protein E7, Human papillomavirus type 16
• Methyltransferases
• METTL3 protein, human

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• DNA-Binding Proteins (genetics)
• Female
• Genetic Therapy
• Human papillomavirus 16 (genetics)
• Human papillomavirus 18 (genetics)
• Humans
• Methyltransferases (metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Oncogene Proteins, Viral (genetics)
• Papillomavirus E7 Proteins (genetics)
• Papillomavirus Infections (virology)
• Proto-Oncogene Proteins c-myc (metabolism)
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• RNA-Binding Proteins (genetics)
• Repressor Proteins (genetics)
• Uterine Cervical Neoplasms (pathology, virology)
• Warburg Effect, Oncologic
• Xenograft Model Antitumor Assays