FTO promotes colorectal cancer progression and chemotherapy resistance via demethylating G6PD/PARP1

作者：Jiyan Wang, Yaya Qiao, Mingming Sun, Huanran Sun, Fei Xie, Hongkai Chang, Yingzhi Wang, Jiaqi Song, Sizhen Lai, Chenxin Yang, Xichuan Li, Shuangping Liu, Xuanzhu Zhao, Kemin Ni, Kewei Meng, Shuai Zhang, Changliang Shan, Chunze Zhang · 发表于：Clinical and Translational Medicine · 年份：2022 · DOI：10.1002/ctm2.772 · 被引用次数：45 · 研究领域：RNA modifications and cancer、Urinary and Genital Oncology Studies

Cytotoxic chemotherapy has long been the backbone of treatment for colorectal cancer (CRC) in patients. In spite of advances in therapy, the 5-year survival rate is still unsatisfactory, mostly due to chemotherapy resistance in the therapy process.1, 2 In our study, we demonstrated that the fat mass and obesity-associated (FTO) protein promotes CRC progression and increases chemotherapy resistance, thus, targeting FTO is a promising strategy for therapy CRC, which not only blocks tumor growth, but also reverses chemotherapy resistance. The m6A modification is a dynamically reversible process, added by methyltransferases (Writers: METTL3, METTL14) and removed by demethylases (Erasers: FTO, ALKBH5). To explore the fundamental role of m6A modification during chemotherapy, we found that the level of m6A modification was decreased in the cells treated with 5-FU and cisplatin, the clinical treatment drugs for colorectal cancer (Figure 1A). Later, we also screened out FTO as the major driver in regulating m6A modification during 5-FU and cisplatin treatment from m6A methyltransferases and demethylases (Figure 1B–D; Figure S1A-C). What's more, we proved that FTO's response to chemotherapeutic drugs depends on its m6A demethylase activity (Figure 1E). Lastly, knockdown of FTO also increased the sensitivity of CRC cells to chemotherapy drugs (Figure 1F; Figure S1D-E). In short, FTO, as a demethylase, responses to chemotherapeutic drugs stimulation is universal. These finding means that...