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

Wenran Dan, Liang Zhong, Lihua Yu, Ling Xiong, Jian Li, Jiao Ye, Xu Luo, Chen Liu, Xuan Chu, Beizhong Liu

Life sciences 2022 Jan 15

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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-RARα 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-RARα. 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 GSK3β, causing autophagy inhibition followed by the suppression of PML-RARα ubiquitylation and degradation, which represses JunB transcriptional activation through PU.1/PML-RARα transcriptional complex to block cell differentiation. Coupled with ATRA or GSK3β inhibitor treatment, genetic or pharmacological inhibition of Skp2 strikingly induces JunB expression by accelerating the degradation of PML-RARα, 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-RARα stabilization and in APL oncogenic functions. We reveal a novel mechanism of PML-RARα degradation and JunB regulation that constitute an important signaling network of Skp2-GSK3β-PML/RARα-JunB. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Citation

Wenran Dan, Liang Zhong, Lihua Yu, Ling Xiong, Jian Li, Jiao Ye, Xu Luo, Chen Liu, Xuan Chu, Beizhong Liu. Skp2 promotes APL progression through the stabilization of oncoprotein PML-RARα and the inhibition of JunB expression. Life sciences. 2022 Jan 15;289:120231