TRIM59 depletion attenuates breast cancer cell survival and metastasis.

TRIM59 is essential for breast cancer cell mesenchymal movement and cell survival by maintaining low cell adhesion and high Wnt signaling of breast cancer cells. TRIM59 stabilizes PDCD10 by inhibiting K63 ubiquitination induced by RNFT1 at the lysine 179 site, and subsequently suppresses p62-selective autophagy degradation. TRIM59 deficiency facilitates PDCD10 degradation to overcome its inhibitory effect on Rho/ROCK signaling, thereby causing hyperactivated MLC and ERM and mesenchymal to amoeboid transition (MAT). TRIM59 deficiency also promotes excessive E-cadherin expression and reduces β-catenin expression, leading to high cell adhesion, low Wnt signaling, and high cell death to ultimately curtail tumor formation and metastasis. ERM, Ezrin (Thr567)/Radixin (Thr564)/Moesin (Thr558); KO, knockout; K63-Ub, lysine 63-linked polyubiquitin; LC3, microtubule-associated protein 1A/1B-light chain 3; MAT, mesenchymal to amoeboid transition; MLC, myosin light chain; PDCD10, programmed cell death protein 10; p-ERM, phosphorylation of ERM; p-MLC, phosphorylation of MLC; p62, phosphotyrosine-independent ligand for the Lck SH2 domain of 62 kDa; Rho/ROCK, Ras homolog/Rho-associated coiled-coil kinase; RNFT1, RING finger and transmembrane domain-containing protein 1; TRIM59, tripartite motif 59; Ub, ubiquitin; WT, wild-type.