PRMT1 inhibition promotes ferroptosis sensitivity via ACSL1 upregulation in acute myeloid leukemia
PRMT1 inhibition promotes ferroptosis sensitivity via ACSL1 upregulation in acute myeloid leukemia
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DOI：
10.1002/mc.23550
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发表时间：
2023-05
影响因子：
4.6
通讯作者：
Lixin Zhou;Xiaoqing Jia;Yingying Shang;Yanni Sun;Zhilong Liu;Jifeng Liu;Wen Jiang;Siyuan Deng;Qiong Yao;Jieping Chen;Hui Li
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文献类型：
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作者：
Lixin Zhou;Xiaoqing Jia;Yingying Shang;Yanni Sun;Zhilong Liu;Jifeng Liu;Wen Jiang;Siyuan Deng;Qiong Yao;Jieping Chen;Hui Li
急性髓细胞白血病（AML）是一种恶性血液病，其死亡率高。因此，迫切需要开发新的AML治疗靶点或药物。铁凋亡是一种由铁依赖性脂质过氧化驱动的调节性细胞死亡形式。最近，铁凋亡已成为靶向癌症（包括AML）的一种新方法。表观遗传失调是AML的一个标志，越来越多的证据表明铁凋亡受表观遗传调节。在这里，我们确定蛋白质精氨酸甲基转移酶1（PRMT 1）作为一个铁凋亡调节剂在AML。I型PRMT抑制剂GSK 3368715在体外和体内促进铁凋亡敏感性。此外，PRMT 1敲除细胞对铁凋亡的敏感性显著增加，表明PRMT 1是AML中GSK 3368715的主要靶点。从机制上讲，GSK 3368715和PRMT 1敲除均上调酰基辅酶A合成酶长链家族成员1（ACSL 1），ACSL 1通过增加脂质过氧化作用作为铁凋亡启动子。敲除ACSL 1降低了GSK 3368715处理后AML细胞的铁凋亡敏感性。此外，GSK 3368715处理降低了全基因组和ACSL 1启动子区域中由PRMT 1介导的主要组蛋白甲基化修饰H4 R3 me 2a的丰度。总体而言，我们的研究结果证明了PRMT 1/ACSL 1轴在铁凋亡中的一个先前未知的作用，并表明了PRMT 1抑制剂和铁凋亡诱导剂组合在AML治疗中的潜在价值和应用。
Acute myeloid leukemia (AML) is a hematological malignancy with an alarming mortality rate. The development of novel therapeutic targets or drugs for AML is urgently needed. Ferroptosis is a form of regulated cell death driven by iron‐dependent lipid peroxidation. Recently, ferroptosis has emerged as a novel method for targeting cancer, including AML. Epigenetic dysregulation is a hallmark of AML, and a growing body of evidence suggests that ferroptosis is subject to epigenetic regulation. Here, we identified protein arginine methyltransferase 1 (PRMT1) as a ferroptosis regulator in AML. The type I PRMT inhibitor GSK3368715 promoted ferroptosis sensitivity in vitro and in vivo. Moreover, PRMT1‐knockout cells exhibited significantly increased sensitivity to ferroptosis, suggesting that PRMT1 is the primary target of GSK3368715 in AML. Mechanistically, both GSK3368715 and PRMT1 knockout upregulated acyl‐CoA synthetase long‐chain family member 1 (ACSL1), which acts as a ferroptosis promoter by increasing lipid peroxidation. Knockout ACSL1 reduced the ferroptosis sensitivity of AML cells following GSK3368715 treatment. Additionally, the GSK3368715 treatment reduced the abundance of H4R3me2a, the main histone methylation modification mediated by PRMT1, in both genome‐wide and ACSL1 promoter regions. Overall, our results demonstrated a previously unknown role of the PRMT1/ACSL1 axis in ferroptosis and suggested the potential value and applications of the combination of PRMT1 inhibitor and ferroptosis inducers in AML treatment.