Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, Anhui, China.
Division of Life Sciences and Medicine, Department of Cancer Radiotherapy, The First Affiliated Hospital of USTC, University of Science and Technology of China (Anhui Provincial Cancer Hospital), Hefei, Anhui, China.
J Cell Mol Med. 2023 Dec;27(24):4118-4132. doi: 10.1111/jcmm.17997. Epub 2023 Oct 13.
N -methyladenosine (m A) modification represents the most abundant internal methylation of eukaryotic RNAs. KIAA1429 acts as a key component of the m A methyltransferase complex, but its function and mechanism in ferroptotic cell death of hepatocellular carcinoma (HCC) are barely defined. We found that KIAA1429 suppression triggered ferroptosis in HCC cells according to increased cell death, iron and MDA levels, C11-BODIPY-positive cells, ROS production and decreased GSH level. Ferroptosis inhibitors ferrostatin-1 (0.5 μM) and liproxstatin-1 (10 μM) blocked KIAA1429 suppression-induced ferroptosis of HCC cells. In addition, overexpressed KIAA1429 notably heightened the activity of cystine/glutamate antiporter (SLC7A11). SLC7A11 up-regulation partially hindered KIAA1429 inhibition-mediated ferroptosis of HCC cells. The regulation SLC7A11 by KIAA1429 was attenuated by global m A inhibitor cycloleucine (40 μM). RNA immunoprecipitation confirmed the binding of KIAA1429 to m A on SLC7A11 transcript. Additionally, it was proven that KIAA1429 inhibition mitigated HCC growth in subcutaneous xenograft mice through SLC7A11. Altogether, our findings first propose that KIAA1429 protects HCC cells from ferroptosis with a m A-dependent post-transcriptional modification of SLC7A11 and offer a novel insight into the dysregulated epi-transcriptomics in the context of HCC.
N6-甲基腺苷（m6A）修饰是真核 RNA 中最丰富的内部甲基化。KIAA1429 作为 m6A 甲基转移酶复合物的关键组成部分发挥作用，但它在肝癌（HCC）铁死亡细胞死亡中的功能和机制尚未明确。我们发现，根据细胞死亡增加、铁和 MDA 水平升高、C11-BODIPY 阳性细胞、ROS 产生减少和 GSH 水平降低，KIAA1429 抑制可触发 HCC 细胞发生铁死亡。铁死亡抑制剂 ferrostatin-1（0.5μM）和 liproxstatin-1（10μM）阻断了 KIAA1429 抑制诱导的 HCC 细胞铁死亡。此外，过表达的 KIAA1429 显著提高了胱氨酸/谷氨酸反向转运蛋白（SLC7A11）的活性。SLC7A11 的上调部分阻碍了 KIAA1429 抑制介导的 HCC 细胞铁死亡。由 KIAA1429 调节的 SLC7A11 被全局 m6A 抑制剂环亮氨酸（40μM）减弱。RNA 免疫沉淀证实 KIAA1429 与 SLC7A11 转录物上的 m6A 结合。此外，证明 KIAA1429 抑制通过 SLC7A11 减轻了皮下异种移植小鼠的 HCC 生长。总之，我们的研究结果首次提出 KIAA1429 通过 SLC7A11 的 m6A 依赖性转录后修饰来保护 HCC 细胞免受铁死亡，并为 HCC 背景下失调的 epi 转录组学提供了新的见解。
