Bioactive peptide inhibits acute myeloid leukemia cell proliferation by downregulating ALKBH5-mediated m(6)A demethylation of EIF4EBP1 and MLST8 mRNA.
Bioactive peptide inhibits acute myeloid leukemia cell proliferation by downregulating ALKBH5-mediated m(6)A demethylation of EIF4EBP1 and MLST8 mRNA.
复制标题
DOI：
10.1007/s13402-022-00666-9
复制
发表时间：
2022-06
影响因子：
6.6
通讯作者：
Su, Xiulan
中科院分区：
文献类型：
--
作者：
Zhang, Le;Su, Xiulan
关键词：
N6-甲基腺苷（m6 A），最普遍的mRNA修饰，在肿瘤发生中起着至关重要的作用。值得注意的是，具有抗肿瘤活性的生物活性肽（BP）引起了越来越多的兴趣。在这里，我们着手研究BP调节的ALKBH 5/MLST 8/EIF 4 EBP 1轴在预防和治疗急性髓细胞白血病（AML）中的潜力。采用MTT法和ApoLive-Glo™法检测BP对AML细胞的生物学效应。通过皮下异种移植模型确定BP在肿瘤生长中的作用。通过甲基化RNA免疫沉淀测序（MeRIP-seq）结合RNA测序（RNA-seq），将ALKBH 5/MLST 8/EIF 4 EBP 1轴确定为AML中的潜在BP靶点。进行蛋白质印迹、RT-qPCR、MeRIP-qPCR、双荧光素酶报告基因和RNA稳定性测定，以验证BP调节的ALKBH 5/MLST 8/EIF 4 EBP 1轴的功能和作用模式。通过TCGA数据分析证实了AML中BP调节的ALKBH 5/MLST 8/EIF 4 EBP 1轴的临床相关性。我们发现BP在体外能抑制AML细胞增殖，促进细胞凋亡，在体内能抑制AML肿瘤生长。从机制上讲，我们发现BP下调ALKBH 5的表达，这反过来又抑制了MLST 8和EIF 4 EBP 1 mRNA的m6 A去甲基化。MLST 8和EIF 4 EBP 1的m6 A水平的降低促进MLST 8和EIF 4 EBP 1 mRNA的衰减，导致AML细胞增殖的抑制。此外，我们发现BP调节的ALKBH 5/MLST 8/EIF 4 EBP 1轴与AML患者的预后密切相关。我们的数据表明，BP可以通过下调ALKBH 5介导的EIF 4 EBP 1和MLST 8 mRNA的m6 A去甲基化来抑制急性髓性白血病细胞增殖，这可能具有预防和治疗这种疾病的潜力。在线版本包含补充材料，可通过10.1007/s13402-022-00666-9获得。
N6-methyladenosine (m6A), the most prevalent mRNA modification, plays an essential role in tumorigenesis. Notably, increasing interest has been directed to bioactive peptides (BPs) with antitumor activities. Here, we set out to investigate the potential of the BP-regulated ALKBH5/MLST8/EIF4EBP1 axis on prevention and treatment of acute myeloid leukemia (AML). The biological effects of BP on AML cells were detected by MTT and ApoLive-Glo™ multiplex assays. The role of BP in tumor growth was determined by a subcutaneous xenograft model. The ALKBH5/MLST8/EIF4EBP1 axis was identified as a potential BP target in AML via methylated RNA immunoprecipitation sequencing (MeRIP-seq) combined with RNA sequencing (RNA-seq). Western blot, RT-qPCR, MeRIP-qPCR, dual-luciferase reporter and RNA stability assays were performed to validate the function and mode of action of the BP-regulated ALKBH5/MLST8/EIF4EBP1 axis. The clinical relevance of the BP-regulated ALKBH5/MLST8/EIF4EBP1 axis in AML was confirmed by TCGA data analysis. We found that BP can inhibit AML cell proliferation and promote apoptosis in vitro, and repress AML tumor growth in vivo. Mechanistically, we found that BP downregulated ALKBH5 expression, which in turn repressed m6A demethylation of MLST8 and EIF4EBP1 mRNAs. Reduction of the m6A levels of MLST8 and EIF4EBP1 facilitated MLST8 and EIF4EBP1 mRNA decay, resulting in inhibition of AML cell proliferation. Furthermore, we found that the BP-regulated ALKBH5/MLST8/EIF4EBP1 axis closely correlates with AML patient prognosis. Our data indicate that BP can inhibit acute myeloid leukemia cell proliferation by downregulating ALKBH5-mediated m6A demethylation of EIF4EBP1 and MLST8 mRNAs, which may have potential to prevent and treat this disease. The online version contains supplementary material available at 10.1007/s13402-022-00666-9.
登录
查看更多内容
影响因子：
5.2
作者：
Kowalski-Chauvel A;Lacore MG;Arnauduc F;Delmas C;Toulas C;Cohen-Jonathan-Moyal E;Seva C
通讯作者：
Seva C
RNA 中的 N6-甲基-腺苷 (m6A)：具有新表观遗传功能的旧修饰
影响因子：
9.5
作者：
Niu, Yamei;Zhao, Xu;Wu, Yong-Sheng;Li, Ming-Ming;Wang, Xiu-Jie;Yang, Yun-Gui
通讯作者：
Yang, Yun-Gui
DOI：
10.1073/pnas.1918986117
发表时间：
2020-08-18
影响因子：
11.1
作者：
Li, Na;Kang, Yuqi;Rana, Tariq M.
通讯作者：
Rana, Tariq M.
影响因子：
37.3
作者：
Chen, Weina;Drakos, Elias;Rassidakis, George Z.
通讯作者：
Rassidakis, George Z.
影响因子：
12.8
作者：
Estey, Elihu H.
通讯作者：
Estey, Elihu H.