Skp2 promotes APL progression through the stabilization of oncoprotein PML-RARα and the inhibition of JunB expression

Aims: To investigate the role of Skp2 and JunB on acute promyelocytic leukemia (APL) progression and the related mechanism.& nbsp;Materials and methods: 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 per -formed to explore Skp2-regulated downstream target genes. Luciferase and co-immunoprecipitation analysis indicated that PML-RAR alpha 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 alpha.& nbsp;Key findings: 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 beta, causing autophagy inhibition followed by the suppression of PML-RAR alpha ubiquitylation and degradation, which represses JunB transcriptional activation through PU.1/PML-RAR alpha transcriptional complex to block cell differentiation. Coupled with ATRA or GSK3 beta inhibitor treatment, genetic or pharmacological inhibition of Skp2 strikingly induces JunB expression by accelerating the degradation of PML-RAR alpha, which contributes to the eradication of APL. Additionally, the expressions of Skp2 and JunB are negatively correlated in mice subcutaneous leukemia xenograft tumors.& nbsp;Significance: Collectively, this study uncovers the roles of Skp2 in PML-RAR alpha stabilization and in APL oncogenic functions. We reveal a novel mechanism of PML-RAR alpha degradation and JunB regulation that constitute an important signaling network of Skp2-GSK3 beta-PML/RAR alpha-JunB.

Automated summary

This study investigates the role of Skp2 and JunB in the progression of acute promyelocytic leukemia (APL) and the related mechanisms. The results show that elevated Skp2 expression promotes APL progression by decreasing the expression of lncRNA HOTAIRM1 and inhibiting GSK3β, leading to autophagy inhibition and the suppression of PML-RARα ubiquitylation and degradation. This represses JunB transcriptional activation through the PU.1/PML-RARα transcriptional complex, blocking cell differentiation. Inhibition of Skp2 induces JunB expression and contributes to the eradication of APL by accelerating the degradation of PML-RARα. The expressions of Skp2 and JunB are negatively correlated in mice subcutaneous leukemia xenograft tumors.