METTL3抑制通过调节SLC7A11表达促进肝细胞癌的放射敏感性。

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2025-01-11 DOI:10.1038/s41419-024-07317-x
Chen Zhang, Tianpeng Yang, Hanbin Chen, Xiaofeng Ding, Huajian Chen, Zhenzhen Liang, Yinlong Zhao, Shumei Ma, Xiaodong Liu
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引用次数: 0

摘要

放疗是晚期肝细胞癌(HCC)的主要治疗方式之一。铁下垂已被证明可促进HCC细胞的放射敏感性,但尚不清楚表观遗传调控是否在这一过程中起作用。在本研究中,我们发现METTL3过表达与预后不良相关。敲低METTL3通过诱导铁下垂促进HCC的放射敏感性。在机制上,METTL3靶向SLC7A11 mRNA上的腺嘌呤(+1795),m6A读本IGF2BP2通过识别和结合m6A位点促进SLC7A11 mRNA的稳定性。此外,METTL3通过m6A/YTHDF2/SOCS2轴降低SLC7A11蛋白的泛素化。此外,体内研究表明,METTL3/IGF2BP2低表达的HCC模型具有更高的放射敏感性。综上所述,我们的研究表明,METTL3以m6A/ igf2bp2依赖的方式调节SLC7A11 mRNA的稳定性,并通过m6A/YTHDF2/SOCS2途径调节SLC7A11蛋白的泛素化,这两种途径都需要METTL3的m6A甲基转移酶活性。METTL3或IGF2BP2可能是HCC放疗的有希望的靶点。
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METTL3 inhibition promotes radiosensitivity in hepatocellular carcinoma through regulation of SLC7A11 expression.

Radiotherapy is one of the main treatment modalities for advanced hepatocellular carcinoma (HCC). Ferroptosis has been shown to promote the radiosensitivity of HCC cells, but it remains unclear whether epigenetic regulations function in this process. In this study, we found that the overexpression of METTL3 was associated with poor prognosis. Knockdown of METTL3 promoted radiosensitivity of HCC by inducing ferroptosis. Mechanistically, METTL3 targeted adenine (+1795) on the SLC7A11 mRNA, and the m6A reader IGF2BP2 promoted SLC7A11 mRNA stability by recognizing and binding to the m6A site. Additionally, METTL3 decreased the ubiquitination of SLC7A11 protein through the m6A/YTHDF2/SOCS2 axis. Furthermore, in vivo studies showed that HCC models with low METTL3/IGF2BP2 expression have higher radiosensitivity. In conclusion, our study suggests that METTL3 regulates the stability of SLC7A11 mRNA in an m6A/IGF2BP2-dependent manner and the ubiquitination of SLC7A11 protein through the m6A/YTHDF2/SOCS2 pathway, both of which require the m6A methyltransferase activity of METTL3. METTL3 or IGF2BP2 may be promising targets for radiotherapy of HCC.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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