Skp2 promotes APL progression through the stabilization of oncoprotein PML-RAR? and the inhibition of JunB expression.
To investigate the role of Skp2 and JunB on acute promyelocytic leukemia (APL) progression and the related mechanism.The expression of Skp2 in NB4 cell line was depleted to explore its effect on proliferation and differentiation both in vitro and in vivo assays. Western blot and quantitative RT-PCR analysis were performed ... to explore Skp2-regulated downstream target genes. Luciferase and co-immunoprecipitation analysis indicated that PML-RAR? inhibited the transactivation of JunB by interacting with the PU.1 protein. The western blot analysis confirmed that Skp2 could maintain the stability of PML-RAR?.We report that the progression of APL and the attenuation of APL sensitivity to ATRA are positively associated with Skp2. Elevated Skp2 expression promotes APL progression by decreasing the expression of lncRNA HOTAIRM1 and inactivation of GSK3?, causing autophagy inhibition followed by the suppression of PML-RAR? ubiquitylation and degradation, which represses JunB transcriptional activation through PU.1/PML-RAR? transcriptional complex to block cell differentiation. Coupled with ATRA or GSK3? inhibitor treatment, genetic or pharmacological inhibition of Skp2 strikingly induces JunB expression by accelerating the degradation of PML-RAR?, which contributes to the eradication of APL. Additionally, the expressions of Skp2 and JunB are negatively correlated in mice subcutaneous leukemia xenograft tumors.Collectively, this study uncovers the roles of Skp2 in PML-RAR? stabilization and in APL oncogenic functions. We reveal a novel mechanism of PML-RAR? degradation and JunB regulation that constitute an important signaling network of Skp2-GSK3?-PML/RAR?-JunB.
Mesh Terms:
Animals, Gene Expression Regulation, Leukemic, HEK293 Cells, Humans, Leukemia, Promyelocytic, Acute, Mice, Mice, Inbred NOD, Mice, SCID, Oncogene Proteins, Fusion, Protein Stability, S-Phase Kinase-Associated Proteins, Transcription Factors, Transcriptional Activation, U937 Cells, Xenograft Model Antitumor Assays
Animals, Gene Expression Regulation, Leukemic, HEK293 Cells, Humans, Leukemia, Promyelocytic, Acute, Mice, Mice, Inbred NOD, Mice, SCID, Oncogene Proteins, Fusion, Protein Stability, S-Phase Kinase-Associated Proteins, Transcription Factors, Transcriptional Activation, U937 Cells, Xenograft Model Antitumor Assays
Life Sci
Date: Jan. 15, 2022
PubMed ID: 34921867
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