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 m 6 A 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.

The role of Insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs) as m6A readers in cancer

“…IGF2BP2 also promotes lymphatic metastasis and epithelial-mesenchymal transition (EMT) of head and neck squamous carcinoma cells by stabilizing slug mRNA in an m 6 A-dependent manner 168 . In addition, human papillomavirus E6/E7 promotes aerobic glycolysis of cervical cancer by stabilizing MYC expression in IGF2BP2-mediated m 6 A-dependent way 169 . In breast cancer stem-like cells (BCSC), aurora kinase A (AURKA) binds to IGF2BP2 and strengthens IGF2BP2 to stabilize DROSHA mRNA in an m 6 A-modified way, thereby increasing BCSC stemness maintenance 170 .…”

New roles of N6-methyladenosine methylation system regulating the occurrence of non-alcoholic fatty liver disease with N6-methyladenosine-modified MYC

“…The m6A regulators regulated the m6A methylation in MYC, affecting the stability and translation efficiency of MYC, and then regulated the expression of MYC, which was an important mechanism for the occurrence and development of cancers ( Wu et al, 2021 ; Zheng et al, 2022 ). The m6A regulators of METTL3/5, FTO, IGF2BP1/2/3, YTHDF2 ( Einstein et al, 2021 ; Iaiza et al, 2021 ; Yang et al, 2021 ; Chen et al, 2022 ; Du et al, 2022 ; Hu et al, 2022 ; Huang et al, 2022 ; Liu et al, 2022 ; Luo and Lin, 2022 ), and so on had been proven to modulate the mechanism. In our study, compared with the healthy control, MYC mRNA levels were lower in both NAFL and NASH, while no differences were found between NAFL and NASH.…”

Synthesis and Anticancer Activity of Rhopaladins’ Analog RPDPD Against the HeLa Human Cervical Cancer Cell Line

“…The studies have shown that the oncogenic potential of high-risk HPV 16 genotypes is determined by the E6 and E7 oncogenes. These two viral oncogenes are often co-expressed in cervical cancer cells and regulate the occurrence and maintenance of cervical cancer ( Hu et al, 2022 ). Their open reading frames are directly involved in regulating the growth of cervical cancer cells, play a key role in the proliferation of cervical cancer cells, and are closely related to the apoptosis of cervical cancer cells ( Wen et al, 2021 ; Zhang et al, 2021 ).…”