Department of Laboratory Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Core Unit of National Clinical Research Center for Laboratory Medicine, Hefei, China.
J Exp Clin Cancer Res. 2023 Jun 20;42(1):151. doi: 10.1186/s13046-023-02732-y.
Glycolysis is the key hallmark of cancer and maintains malignant tumor initiation and progression. The role of N6-methyladenosine (m6A) modification in glycolysis is largely unknown. This study explored the biological function of m6A methyltransferase METTL16 in glycolytic metabolism and revealed a new mechanism for the progression of Colorectal cancer (CRC).
The expression and prognostic value of METTL16 was evaluated using bioinformatics and immunohistochemistry (IHC) assays. The biological functions of METTL16 in CRC progression was analyzed in vivo and in vitro. Glycolytic metabolism assays were used to verify the biological function of METTL16 and Suppressor of glucose by autophagy (SOGA1). The protein/RNA stability, RNA immunoprecipitation (RIP), Co-immunoprecipitation (Co-IP) and RNA pull-down assays were used to explore the potential molecular mechanisms.
SOGA1 is a direct downstream target of METTL16 and involved in METTL16 mediated glycolysis and CRC progression. METTL16 significantly enhances SOGA1 expression and mRNA stability via binding the "reader" protein insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1). Subsequently, SOGA1 promotes AMP-activated protein kinase (AMPK) complex ubiquitination, inhibits its expression and phosphorylation, thus upregulates pyruvate dehydrogenase kinase 4 (PDK4), a crucial protein controlling glucose metabolism. Moreover, Yin Yang 1 (YY1) can transcriptionally inhibit the expression of METTL16 in CRC cells by directly binding to its promoter. Clinical data showed that METTL16 expression is positively correlated to SOGA1 and PDK4, and is associated with poor prognosis of CRC patients.
Our findings suggest that METTL16/SOGA1/PDK4 axis might be promising therapeutic targets for CRC.
糖酵解是癌症的关键标志，维持着恶性肿瘤的起始和进展。N6-甲基腺苷（m6A）修饰在糖酵解中的作用在很大程度上是未知的。本研究探讨了 m6A 甲基转移酶 METTL16 在糖酵解代谢中的生物学功能，并揭示了结直肠癌（CRC）进展的新机制。
使用生物信息学和免疫组织化学（IHC）检测评估 METTL16 的表达和预后价值。在体内和体外分析 METTL16 在 CRC 进展中的生物学功能。使用糖酵解代谢测定验证 METTL16 和自噬抑制葡萄糖（SOGA1）的生物学功能。蛋白质/RNA 稳定性、RNA 免疫沉淀（RIP）、共免疫沉淀（Co-IP）和 RNA 下拉测定用于探索潜在的分子机制。
SOGA1 是 METTL16 的直接下游靶标，参与 METTL16 介导的糖酵解和 CRC 进展。METTL16 通过结合“阅读器”蛋白胰岛素样生长因子 2 mRNA 结合蛋白 1（IGF2BP1），显著增强 SOGA1 的表达和 mRNA 稳定性。随后，SOGA1 促进 AMP 激活的蛋白激酶（AMPK）复合物泛素化，抑制其表达和磷酸化，从而上调丙酮酸脱氢酶激酶 4（PDK4），这是控制葡萄糖代谢的关键蛋白。此外，Yin Yang 1（YY1）可以通过直接结合其启动子转录抑制 CRC 细胞中 METTL16 的表达。临床数据表明，METTL16 表达与 SOGA1 和 PDK4 呈正相关，与 CRC 患者的不良预后相关。
我们的研究结果表明，METTL16/SOGA1/PDK4 轴可能是 CRC 的有前途的治疗靶点。
