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TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10.

ABSTRACT: Cancer cells adopt various modes of migration during metastasis. How the ubiquitination machinery contributes to cancer cell motility remains underexplored. Here, we report that tripartite motif (TRIM) 59 is frequently up-regulated in metastatic breast cancer, which is correlated with advanced clinical stages and reduced survival among breast cancer patients. TRIM59 knockdown (KD) promoted apoptosis and inhibited tumor growth, while TRIM59 overexpression led to the opposite effects. Importantly, we uncovered TRIM59 as a key regulator of cell contractility and adhesion to control the plasticity of metastatic tumor cells. At the molecular level, we identified programmed cell death protein 10 (PDCD10) as a target of TRIM59. TRIM59 stabilized PDCD10 by suppressing RING finger and transmembrane domain-containing protein 1 (RNFT1)-induced lysine 63 (K63) ubiquitination and subsequent phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa (p62)-selective autophagic degradation. TRIM59 promoted PDCD10-mediated suppression of Ras homolog family member A (RhoA)-Rho-associated coiled-coil kinase (ROCK) 1 signaling to control the transition between amoeboid and mesenchymal invasiveness. PDCD10 overexpression or administration of a ROCK inhibitor reversed TRIM59 loss-induced contractile phenotypes, thereby accelerating cell migration, invasion, and tumor formation. These findings establish the rationale for targeting deregulated TRIM59/PDCD10 to treat breast cancer.

SUBMITTER: Tan P

PROVIDER: S-EPMC6245796 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10.

Tan Peng P Ye Youqiong Y He Lian L Xie Jiansheng J Jing Ji J Ma Guolin G Pan Hongming H Han Leng L Han Weidong W Zhou Yubin Y

PLoS biology 20181108 11

Cancer cells adopt various modes of migration during metastasis. How the ubiquitination machinery contributes to cancer cell motility remains underexplored. Here, we report that tripartite motif (TRIM) 59 is frequently up-regulated in metastatic breast cancer, which is correlated with advanced clinical stages and reduced survival among breast cancer patients. TRIM59 knockdown (KD) promoted apoptosis and inhibited tumor growth, while TRIM59 overexpression led to the opposite effects. Importantly, ...[more]

PMID: 30408026

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Dataset Information

TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10.

Publications

TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10.

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