Department of Medical Oncology and Biomedical Research Center, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Center for Translational Cancer Research, Institute of Biosciences and Technology, College of Medicine, Texas A&M University, Houston, Texas, United States of America.
PLoS Biol. 2018 Nov 8;16(11):e3000051. doi: 10.1371/journal.pbio.3000051. eCollection 2018 Nov.
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.
癌细胞在转移过程中采用各种迁移模式。泛素化机制如何促进癌细胞的迁移仍未得到充分探索。在这里，我们报告三基序（TRIM）59 在转移性乳腺癌中经常上调，这与乳腺癌患者的晚期临床阶段和降低的生存率相关。TRIM59 敲低（KD）促进细胞凋亡并抑制肿瘤生长，而 TRIM59 过表达则产生相反的效果。重要的是，我们发现 TRIM59 是控制细胞收缩和黏附的关键调节剂，以控制转移性肿瘤细胞的可塑性。在分子水平上，我们确定程序性细胞死亡蛋白 10（PDCD10）是 TRIM59 的一个靶标。TRIM59 通过抑制环指和跨膜域蛋白 1（RNFT1）诱导的赖氨酸 63（K63）泛素化和随后的非磷酸酪氨酸依赖性配体结合 62 kDa（p62）选择性自噬降解来稳定 PDCD10。TRIM59 促进 PDCD10 介导的 Ras 同源家族成员 A（RhoA）-Rho 相关卷曲螺旋激酶（ROCK）1 信号的抑制，以控制阿米巴样和间充质侵袭之间的转变。PDCD10 过表达或 ROCK 抑制剂的给药逆转了 TRIM59 缺失诱导的收缩表型，从而加速了细胞迁移、侵袭和肿瘤形成。这些发现为靶向失调的 TRIM59/PDCD10 治疗乳腺癌提供了依据。
