N6-methyladenosine-modified SENP1, identified by IGF2BP3, is a novel molecular marker in acute myeloid leukemia and aggravates progression by activating AKT signal via de-SUMOylating HDAC2

作者全名：Wen, Diguang; Xiao, Hang; Gao, Yueyi; Zeng, Hanqing; Deng, Jianchuan

作者地址：[Wen, Diguang; Xiao, Hang; Gao, Yueyi; Zeng, Hanqing; Deng, Jianchuan] Chongqing Med Univ, Affiliated Hosp 2, Dept Hematol, Chongqing 400010, Peoples R China

通信作者：Zeng, HQ; Deng, JC (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Hematol, Chongqing 400010, Peoples R China.

来源：MOLECULAR CANCER

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001236242100001

JCR分区：Q1

影响因子：27.7

年份：2024

卷号：23

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：Acute myeloid leukemia; SUMO; SENP1; m6A

摘要：Background Elevated evidence suggests that the SENPs family plays an important role in tumor progression. However, the role of SENPs in AML remains unclear.Methods We evaluated the expression pattern of SENP1 based on RNA sequencing data obtained from OHSU, TCGA, TARGET, and MILE datasets. Clinical samples were used to verify the expression of SENP1 in the AML cells. Lentiviral vectors shRNA and sgRNA were used to intervene in SENP1 expression in AML cells, and the effects of SENP1 on AML proliferation and anti-apoptosis were detected using in vitro and in vivo models. Chip-qPCR, MERIP-qPCR, CO-IP, RNA pulldown, and dual-luciferase reporter gene assays were used to explore the regulatory mechanisms of SNEP1 in AML.Results SENP1 was significantly upregulated in high-risk AML patients and closely related to poor prognosis. The AKT/mTOR signaling pathway is a key downstream pathway that mediates SENP1's regulation of AML proliferation and anti-apoptosis. Mechanistically, the CO-IP assay revealed binding between SENP1 and HDAC2. SUMO and Chip-qPCR assays suggested that SENP1 can desumoylate HDAC2, which enhances EGFR transcription and activates the AKT pathway. In addition, we found that IGF2BP3 expression was upregulated in high-risk AML patients and was positively correlated with SENP1 expression. MERIP-qPCR and RIP-qPCR showed that IGF2BP3 binds SENP1 3-UTR in an m6A manner, enhances SENP1 expression, and promotes AKT pathway conduction.Conclusions Our findings reveal a distinct mechanism of SENP1-mediated HDAC2-AKT activation and establish the critical role of the IGF2BP3/SENP1signaling axis in AML development.

基金机构：Natural Science Foundation of Chongqing, China [2021jcyj-msxmX0064]; Key Project of Natural Science Foundation of Chongqing [CSTB2023NSCQ-LZX0052]

基金资助正文：This study was sponsored by the Natural Science Foundation of Chongqing, China Grant No. 2021jcyj-msxmX0064; the Key Project of Natural Science Foundation of Chongqing, No. CSTB2023NSCQ-LZX0052.