Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Department of Gastroenterology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.
Cell Death Dis. 2023 Nov 23;14(11):760. doi: 10.1038/s41419-023-06273-2.
Lipid metabolism is the key to ferroptosis susceptibility. However, little is known about the underlying mechanisms in osteosarcoma cells. Functional restriction of bromodomain-containing protein 4 (BRD4) reduced the susceptibility to erastin-induced ferroptosis of osteosarcoma cells both in vitro and in vivo. Mechanically, BRD4 controls the splicing efficiency of the RNA precursor (pre-mACSL3) of ACSL3 (ACSL3) by recruiting serinerich/threonine protein kinase 2 (SRPK2) to assemble the splicing catalytic platform. Moreover, the AMP-binding domain of ACSL3 significantly influences arachidonic acid synthesis and thus determines the susceptibility to erastin-induced ferroptosis. Overall, we found a BRD4-mediated pre-mACSL3 splicing influences erastin-induced ferroptosis by affecting arachidonic acid synthesis in osteosarcoma cells. Data in this study fills some of the gap in understanding the post-transcriptional regulatory mechanisms of ACSL3 and provides new insights into the mechanisms of lipid metabolism regulation and its effect on susceptibility to ferroptosis in osteosarcoma cells.
脂质代谢是铁死亡易感性的关键。然而，骨肉瘤细胞中潜在的机制知之甚少。溴结构域蛋白 4（BRD4）的功能限制减少了骨肉瘤细胞对 erastin 诱导的铁死亡的易感性，无论是在体外还是体内。在机制上，BRD4 通过招募丝氨酸/苏氨酸蛋白激酶 2（SRPK2）组装剪接催化平台，控制 ACSL3（ACSL3）的 RNA 前体（pre-mACSL3）的剪接效率。此外，ACSL3 的 AMP 结合域显著影响花生四烯酸的合成，从而决定了对 erastin 诱导的铁死亡的敏感性。总的来说，我们发现 BRD4 介导的 pre-mACSL3 剪接通过影响骨肉瘤细胞中花生四烯酸的合成来影响 erastin 诱导的铁死亡。本研究中的数据填补了理解 ACSL3 的转录后调控机制的一些空白，并为脂质代谢调节及其对骨肉瘤细胞铁死亡易感性的影响机制提供了新的见解。
