SUMO特异性蛋白酶1(SENP1)与急性髓性白血病(AML)之间的遗传关联已得到验证。然而,SENP1影响AML增殖的机制,凋亡,自噬仍然未知。检测AML患者SENP1和聚嘧啶束结合蛋白1(PTBP1)水平,AML细胞系,和异种移植组织。SENP1对AML增殖的影响,凋亡,和BECN1依赖性自噬通过体外和体内功能缺失或获得实验进行评估。使用免疫沉淀(IP)的SUMO化分析,RNA下拉,RIP,和RNA稳定性分析用于探索SENP1在AML发生发展中的分子机制。AML样品中SENP1水平升高。沉默SENP1阻碍了AML的发展,如AML细胞中SENP1耗竭导致的增殖抑制和G1期停滞和凋亡的促进所证明的。此外,沉默SENP1可抑制AML细胞中BECN1-脱位自噬。此外,BECN1或PTBP1的过表达部分中和了SENP1敲低对AML细胞行为的影响。机械上,SENP1介导PTBP1去SUMO化,然后直接与BECN1mRNA相互作用并增强其稳定性。体内实验进一步证实了SENP1抑制对AML发展的抑制作用。总的来说,SENP1/PTBP1/BECN1信号轴已被确定为增强AML治疗的重要治疗靶标.
Genetic association between SUMO-specific protease 1 (SENP1) and acute myeloid leukemia (AML) has been validated. However, the mechanism by which SENP1 affects AML proliferation, apoptosis, and autophagy remains unknown. The levels of SENP1 and polypyrimidine tract-binding protein 1 (
PTBP1) were measured in AML patients, AML cell lines, and xenograft tissues. The effects of SENP1 on AML proliferation, apoptosis, and BECN1-dependent autophagy were assessed through in vitro and in vivo loss- or gain-of-function experiments. SUMOylation analysis using immunoprecipitation (IP), RNA pull-down, RIP, and RNA stability assays were used to explore the molecular mechanism of SENP1 in AML development. The SENP1 level was elevated in AML samples. Silencing SENP1 impeded the development of AML, as evidenced by the inhibition of proliferation and promotion of G1 phase arrest and apoptosis resulting from SENP1 depletion in AML cells. Moreover, silencing of SENP1 restrained BECN1-depentent autophagy in AML cells. In addition, the overexpression of BECN1 or
PTBP1 partially neutralized the effect of SENP1 knockdown on AML cell behavior. Mechanistically, SENP1 mediated
PTBP1 deSUMOylation, which then directly interacted with BECN1 mRNA and enhanced its stability. In vivo experiments further confirmed the repressive effects of SENP1 suppression on AML development. Collectively, the SENP1/
PTBP1/BECN1 signaling axis has been identified as a significant therapeutic target for enhancing AML treatment.