Department of Pathology, Xuzhou Medical University, 209 Tong-shan Road, Xuzhou 221004, Jiangsu, China.
Jiangsu Key Laboratory of New drug and Clinical Pharmacy, Xuzhou Medical University, 209 Tong-shan Road, Xuzhou 221004, Jiangsu, China.
Pharmacol Res. 2023 Sep;195:106863. doi: 10.1016/j.phrs.2023.106863. Epub 2023 Jul 20.
Human papillomavirus (HPV) infection is a causative agent of cervical cancer (CC). N6-methyladenosine (m6A) modification is implicated in carcinogenesis and tumor progression. However, the involvement of m6A modification in HPV-involved CC remains unclear. Here we showed that HPV E6/7 oncoproteins affected the global m6A modification and E7 specifically promoted the expression of ALKBH5. We found that ALKBH5 was significantly upregulated in CC and might serve as a valuable prognostic marker. Forced expression of ALKBH5 enhanced the malignant phenotypes of CC cells. Mechanistically, we discovered that E7 increased ALKBH5 expression through E2F1-mediated activation of the H3K27Ac and H3K4Me3 histone modifications, as well as post-translational modification mediated by DDX3. ALKBH5-mediated m6A demethylation enhanced the expression of PAK5. The m6A reader YTHDF2 bound to PAK5 mRNA and regulated its stability in an m6A-dependent manner. Moreover, ALKBH5 promoted tumorigenesis and metastasis of CC by regulating PAK5. Overall, our findings herein demonstrate a significant role of ALKBH5 in CC progression in HPV-positive cells. Thus, we propose that ALKBH5 may serve as a prognostic biomarker and therapeutic target for CC patients.
人乳头瘤病毒（HPV）感染是宫颈癌（CC）的致病因子。N6-甲基腺苷（m6A）修饰与致癌作用和肿瘤进展有关。然而，m6A 修饰在 HPV 相关 CC 中的参与仍不清楚。在这里，我们表明 HPV E6/7 癌蛋白影响全局 m6A 修饰，并且 E7 特异性促进 ALKBH5 的表达。我们发现 ALKBH5 在 CC 中明显上调，可能作为有价值的预后标志物。强制表达 ALKBH5 增强了 CC 细胞的恶性表型。在机制上，我们发现 E7 通过 E2F1 介导的 H3K27Ac 和 H3K4Me3 组蛋白修饰以及 DDX3 介导的翻译后修饰来增加 ALKBH5 的表达。ALKBH5 介导的 m6A 去甲基化增强了 PAK5 的表达。m6A 阅读器 YTHDF2 与 PAK5 mRNA 结合，并以 m6A 依赖的方式调节其稳定性。此外，ALKBH5 通过调节 PAK5 促进 CC 的发生和转移。总体而言，我们的研究结果表明 ALKBH5 在 HPV 阳性细胞的 CC 进展中具有重要作用。因此，我们提出 ALKBH5 可作为 CC 患者的预后生物标志物和治疗靶标。
