CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity

Youzhou Sang,Yanxin Li,Shi-Yuan Cheng,Bo Yu,Angel A. Alvarez,Bo Hu,Haizhong Feng,Yingwen Zhang,Weiwei Zhang

doi:10.1038/s41467-019-12001-2

Abstract

Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable, thus justifying the urgent need of new therapies. CDK5 plays a critical role in GBM and is a potential target for GBM. However, the mechanism by which CDK5 promotes GBM tumorigenicity remains largely unknown. Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis–trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. Correlative expressions of the components of this pathway are clinically prognostic. Our findings suggest targeting CDK5/TRIM59 signaling axis as a putative strategy for treating GBM.

Highlights

Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable, justifying the urgent need of new therapies
We report a critical role of Tripartite motif-containing 59 (TRIM59) as a substrate of Cyclin-dependent kinase 5 (CDK5) in epidermal growth factor receptor (EGFR)-driven GBM
We found that nuclear translocation of TRIM59 WT or S308D mutant but not S308A was markedly reduced in LN229/EGFRvIII cells treated with Juglone inhibitor of PIN1 (Supplementary Fig. 6)

Summary

Introduction

Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable, justifying the urgent need of new therapies. CDK5 plays a critical role in GBM and is a potential target for GBM. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis–trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. In GBM, CDK5 is highly expressed in clinical tumors[17] and a critical regulator of GBM tumorigenesis[16]. Nuclear TRIM59 promotes the tumorsuppressive histone variant macroH2A1 ubiquitination and degradation, leading to enhanced STAT3 signaling activation and tumorigenicity

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Results

Conclusion