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.
Highlights
The tripartite motif (TRIM) protein family of E3 ubiquitin ligases is intimately implicated in tumorigenesis by enhancing gene translocation and fusion [1,2], promoting cell cycle arrest through deregulation of tumor protein 53 (p53) and cyclin-dependent kinase (CDK) inhibitors degradation [3,4], or regulating tumor metabolic homeostasis with melanoma antigen family proteins [5]
Changes in cell morphology are critical for cancer cell motility and metastasis, and this process requires spatiotemporal control of the turnover or stabilization of signaling components that regulate cell polarity
We show that TRIM59 regulates the degradation of PDCD10, which is involved in programmed cell death and is the main factor for driving the pathogenesis of the devastating familial cerebral cavernous malformation (CCM) disease
Summary
The tripartite motif (TRIM) protein family of E3 ubiquitin ligases is intimately implicated in tumorigenesis by enhancing gene translocation and fusion [1,2], promoting cell cycle arrest through deregulation of tumor protein 53 (p53) and cyclin-dependent kinase (CDK) inhibitors degradation [3,4], or regulating tumor metabolic homeostasis with melanoma antigen family proteins [5]. Among all the TRIM genes, TRIM59 was found to be the only member displaying marked up-regulation across all the 12 cancer types, a discovery that concurs with the recent findings that TRIM59 promotes the progression of prostate cancer [8], lung cancer [9], and gastric cancer [10] While these earlier studies are primarily centered on establishing the correlations of TRIM59 with cancer hallmarks such as cell cycle progression and apoptosis, the direct targets of TRIM59 and the molecular mechanisms underpinning the pro-oncogenic role of TRIM59 in breast cancer, its involvement in advanced stages of malignant transformation (cancer invasion and metastasis), remain largely unexplored
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