TY  - JOUR
T1  - Neddylylation Inhibitor MLN4924 Reactivates TRIM58 through LINC01128-Dependent DNMT1 Sequestration in Acute Myeloid Leukemia
A1  - Hannah Scott
A1  - Lucas Green
JF  - Pharmaceutical Sciences and Drug Design
JO  - Pharm Sci Drug Des
SN  - 3062-4428
Y1  - 2021
VL  - 1
IS  - 1
DO  - 10.51847/rR232vnf8j
SP  - 119
EP  - 134
N2  - This work aimed to clarify how MLN4924 influences acute myeloid leukemia (AML) biology, focusing on its ability to regulate TRIM58 promoter methylation and the downstream molecular events. RT-qPCR and Western blotting were applied to quantify transcript and protein levels, while methylation-sensitive restriction enzyme–qPCR assessed DNA methylation status. RNA sequencing was used to screen for lncRNAs with altered expression. Subcellular fractionation followed by PCR identified transcript localization. Chromatin immunoprecipitation and RNA immunoprecipitation were used to explore protein–DNA and protein–RNA interactions. An in vivo xenograft system was employed to examine tumor behavior, and immunohistochemistry was used to analyze protein expression in tissue samples. TRIM58 expression was reduced in AML and linked to hypermethylation of its promoter region, an effect reversed by MLN4924. Functional assays showed that TRIM58 contributed to MLN4924-triggered apoptotic signaling by suppressing AKT activation. MLN4924 elevated levels of the tumor-inhibitory lncRNA LINC01128, whose forced expression reproduced the TRIM58-associated antiproliferative and pro-apoptotic actions, including modulation of BAX/BCL-2. LINC01128, predominantly nuclear, interacted with DNMT1 and helped drive demethylation of the TRIM58 promoter, defining a new regulatory mechanism. Knockdown of TRIM58 weakened the impact of MLN4924 on AKT phosphorylation and reduced the subsequent apoptotic response. These findings indicate that MLN4924 enhances LINC01128 expression, enabling it to sequester DNMT1 and prevent TRIM58 promoter methylation, ultimately inhibiting AML progression.
UR  - https://galaxypub.co/article/neddylylation-inhibitor-mln4924-reactivates-trim58-through-linc01128-dependent-dnmt1-sequestration-i-9v3v8zw98bypndx
ER  -