SIRT1 regulates the phosphorylation and degradation of P27 by deacetylating CDK2 to promote T-cell acute lymphoblastic leukemia progression.
SIRT1 regulates the phosphorylation and degradation of P27 by deacetylating CDK2 to promote T-cell acute lymphoblastic leukemia progression.
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SIRT1通过去乙酰CDK2调节P27的磷酸化和降解促进T细胞急性淋巴细胞白血病进展
DOI：
10.1186/s13046-021-02071-w
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发表时间：
2021-08-18
期刊：
影响因子：
--
通讯作者：
Liang A
中科院分区：
文献类型：
--
作者：
Wang F;Li Z;Zhou J;Wang G;Zhang W;Xu J;Liang A
尽管临床治疗取得了显著进展，但大多数T细胞急性淋巴细胞白血病（T-ALL）患者的临床结果仍然很差，因为即使在完全缓解后，复发的风险也很高。先前的研究表明，NAD依赖性去乙酰化酶sirtuin 1（SIRT 1）在血液恶性肿瘤中具有双重作用，根据肿瘤类型作为肿瘤抑制剂或肿瘤促进剂。然而，SIRT 1在T-ALL白血病发生中的表达和功能尚不清楚。使用公开的RNA-seq数据、Notch 1驱动的T-ALL小鼠模型和γ-分泌酶抑制剂来鉴定T-ALL中的SIRT 1表达。我们用ShRNAs敲低SIRT 1的表达，并评估SIRT 1缺陷对细胞增殖、集落形成、细胞周期和凋亡的影响。使用转基因SIRT 1敲除小鼠来确定SIRT 1在体内的功能。采用RT-PCR、western blot、免疫共沉淀和泛素化分析检测SIRT 1、p27和CDK 2的表达及其相互作用。SIRT 1蛋白表达与Notch 1的激活呈正相关。SIRT 1表达下调可抑制T-ALL细胞系的增殖和集落形成，而SIRT 1过表达可逆转这种抑制作用。SIRT 1沉默可延长T-ALL模型小鼠的寿命。我们证明了p27参与了SIRT 1沉默诱导的细胞周期阻滞的下游机制。SIRT 1通过去乙酰化CDK 2增加Thr 187上p27的磷酸化，并增强p27和SKP 2之间的相互作用，导致p27的降解。我们的研究结果表明，SIRT 1是T-ALL中一个有前途的靶点，并提供了SIRT 1上调和p27下调之间的机制联系。在线版本包含补充材料，可通过10.1186/s13046-021-02071-w获得。
Despite marked advances in the clinical therapies, clinical outcome of most T-cell acute lymphoblastic leukemia (T-ALL) patients remains poor, due to the high risk of relapse, even after complete remission. Previous studies suggest that the NAD-dependent deacetylase sirtuin 1 (SIRT1) has a dual role in hematologic malignancies, acting as a tumor suppressor or tumor promoter depending on the tumor type. However, little is known about the expression and functions of SIRT1 in T-ALL leukemogenesis. Public RNA-seq data, a Notch1 driven T-ALL mouse model and γ-secretase inhibitor were used to identify SIRT1 expression in T-ALL. We knocked down SIRT1 expression with ShRNAs and assessed the impacts of SIRT1 deficiency on cell proliferation, colony formation, the cell cycle and apoptosis. Transgenic SIRT1 knockout mice were used to determine the function of SIRT1 in vivo. RT-PCR, western blot, co-immunoprecipitation and ubiquitination analyses were used to detect SIRT1, p27 and CDK2 expression and their interactions. SIRT1 protein expression was positively correlated with the activation of Notch1. Downregulation of SIRT1 expression suppressed the proliferation and colony formation of T-ALL cell lines, which was reversed by SIRT1 overexpression. SIRT1 silencing prolonged the lifespan of T-ALL model mice. We demonstrated that p27 was involved in the downstream mechanism of cell cycle arrest induced by silencing SIRT1. SIRT1 increased the phosphorylation of p27 on Thr187 by deacetylating CDK2 and enhanced the interaction between p27 and SKP2 leading to the degradation of p27. Our findings suggest that SIRT1 is a promising target in T-ALL and offer a mechanistic link between the upregulation of SIRT1 and downregulation of p27. The online version contains supplementary material available at 10.1186/s13046-021-02071-w.
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影响因子：
14.9
作者：
Mateo F;Vidal-Laliena M;Canela N;Zecchin A;Martínez-Balbás M;Agell N;Giacca M;Pujol MJ;Bachs O
通讯作者：
Bachs O
影响因子：
4.8
作者：
Komatsu, N;Watanabe, T;Ozawa, K
通讯作者：
Ozawa, K
SIRT2 通过损害 Skp2 介导的 p27 降解抑制非小细胞肺癌细胞生长
影响因子：
--
作者：
Li Z;Huang J;Yuan H;Chen Z;Luo Q;Lu S
通讯作者：
Lu S
影响因子：
21.3
作者：
Carrano, AC;Eytan, E;Pagano, M
通讯作者：
Pagano, M
影响因子：
20.3
作者：
Joshi, Ila;Minter, Lisa M.;Osborne, Barbara A.
通讯作者：
Osborne, Barbara A.