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

• DOI: 10.1038/s41467-019-12001-2
• Publication Date: 2019-09-09T14:22:03Z
• Authors: Youzhou Sang; Yanxin Li; Yingwen Zhang; Angel A. Alvarez; Bo Yu; Weiwei Zhang; Bo Hu; Shi-Yuan Cheng; Haizhong Feng
• Keywords: STAT3 Transcription Factor; Carcinogenesis; Science; Article; Histones; Tripartite Motif Proteins; Mice; 03 medical and health sciences; Cell Line, Tumor; Metalloproteins; Animals; Humans; Phosphorylation; 0303 health sciences; Brain Neoplasms; Q; Intracellular Signaling Peptides and Proteins; Membrane Proteins; Cyclin-Dependent Kinase 5; 3. Good health; Gene Expression Regulation, Neoplastic; NIMA-Interacting Peptidylprolyl Isomerase; HEK293 Cells; Female; Glioblastoma; Signal Transduction

AbstractDespite 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.