CircZBTB46 Protects Acute Myeloid Leukemia Cells from Ferroptotic Cell Death by Upregulating SCD.
CircZBTB46 Protects Acute Myeloid Leukemia Cells from Ferroptotic Cell Death by Upregulating SCD.
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作者：
寻找新的急性髓系白血病（AML）诊断、鉴别诊断和治疗靶点的生物标志物，以制定更有效的监测和治疗方案是当务之急。铁凋亡是一种重要的铁依赖性调节细胞死亡，由脂质过氧化氢过度积累驱动。越来越多的证据已经证明，失调的铁凋亡与肿瘤进展有关，并且正在成为治疗AML的新兴治疗靶点。然而，circRNA对铁凋亡和AML发展的影响仍不清楚。在这项研究中，我们提供了第一条证据，证明circZBTB46是一种重要的致癌circRNA，也是AML的诊断或预后生物标志物。CircZBTB46在促进SCD表达以保护AML细胞免于铁凋亡细胞死亡中发挥关键作用。重要的是，我们的研究结果可能提供一个潜在的治疗靶点，circZBTB46，以扩大人类AML的治疗选择，特别是关于与铁凋亡诱导剂联合治疗的使用。环状RNA（circRNA）已被证明与血液恶性肿瘤的肿瘤发生和治疗反应密切相关。然而，circRNA在急性髓系白血病（AML）中的生物学功能和临床意义在很大程度上仍然未知。分析CircRNA微阵列数据集以筛选AML患者中差异表达的circRNA。发现circZBTB46在AML患者和AML细胞中显著上调。此外，circZBTB46的表达与AML患者的分期有关，对AML的诊断具有较高的敏感性和特异性。circZBTB46的沉默抑制AML细胞增殖并诱导细胞周期停滞。重要的是，circZBTB46的消耗显著增加AML细胞中的铁凋亡并增强RSL3诱导的铁凋亡。从机制上讲，circZBTB46上调硬脂酰辅酶A去饱和酶1（SCD）的表达，可能是通过充当miRNA海绵。最后，circZBTB46敲低抑制了体内AML的肿瘤生长。综上所述，circZBTB46通过上调SCD保护AML细胞免于铁凋亡并促进增殖，因此表明circZBTB46可能是AML的潜在治疗靶点。
It is urgent to identify new biomarkers for diagnosis, prognostication, and therapeutic targets of acute myeloid leukemia (AML) so as to develop more effective surveillance and treatment programs. Ferroptosis is a crucial, iron-dependent regulated cell death driven by excessive accumulation of lipid hydroperoxides. Accumulating evidence has proven that dysregulated ferroptosis is implicated in tumor progression and is becoming an emerging therapeutic target for the treatment of AML. However, the effect of circRNAs on ferroptosis and the development of AML remain unclear. In this study, we provide the first line of evidence that circZBTB46 is an important oncogenic circRNA as well as a diagnostic or prognostic biomarker for AML. CircZBTB46 exerts a critical role in promoting the expression of SCD to protect AML cells from ferroptotic cell death. Importantly, our findings may offer a potential therapeutic target, circZBTB46, to broaden treatment options for human AML, especially concerning the use of combined treatment with ferroptosis inducers. Circular RNAs (circRNAs) have been shown to be closely linked to the tumorigenesis and treatment response of hematological malignancies. However, the biological functions and clinical implications of circRNAs in acute myeloid leukemia (AML) remain largely unknown. CircRNA microarray datasets were analyzed to screen differentially expressed circRNAs in AML patients. It was found that circZBTB46 was significantly upregulated in AML patients and AML cells. Moreover, the expression of circZBTB46 was associated with the stages of AML patients and showed high sensitivity and specificity for diagnosing AML. Silencing of circZBTB46 inhibited AML cell proliferation and induced cell cycle arrest. Importantly, the depletion of circZBTB46 notably increased ferroptosis and enhanced RSL3-induced ferroptosis in AML cells. Mechanistically, circZBTB46 upregulated the expression of stearoyl-CoA desaturase 1 (SCD) possibly by acting as a miRNA sponge. Finally, the circZBTB46 knockdown repressed the tumor growth of AML in vivo. In conclusion, circZBTB46 protects AML cells from ferroptosis and promotes the proliferation by upregulating SCD, thus suggesting that circZBTB46 may be a potential therapeutic target for AML.
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影响因子：
8.1
作者：
通讯作者：
--
ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
5.6
作者：
Lai, Xingrong;Sun, Yanhua;Zhang, Xuedi;Wang, Dan;Wang, Jialing;Wang, Haihua;Zhao, Yao;Liu, Xinling;Xu, Xin;Song, Haoran;Ping, Wenjia;Sun, Yanli;Hu, Zhenbo
通讯作者：
Hu, Zhenbo
影响因子：
3
作者：
Cheng, P.;Lu, P.;Cheng, H.
通讯作者：
Cheng, H.
影响因子：
12.8
作者：
Estey, Elihu H.
通讯作者：
Estey, Elihu H.