TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10.
TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10.
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DOI：
10.1371/journal.pbio.3000051
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发表时间：
2018-11
期刊：
影响因子：
9.8
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Tan P;Ye Y;He L;Xie J;Jing J;Ma G;Pan H;Han L;Han W;Zhou Y
癌细胞在转移过程中采用多种迁移方式。泛素化机制如何促进癌细胞运动仍有待探索。在此，我们报告三联基序 (TRIM) 59 在转移性乳腺癌中频繁上调，这与乳腺癌患者的晚期临床分期和生存率降低相关。 TRIM59敲低（KD）促进细胞凋亡并抑制肿瘤生长，而TRIM59过表达则导致相反的效果。重要的是，我们发现 TRIM59 作为细胞收缩性和粘附性的关键调节因子来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) 作为 TRIM59 的靶标。 TRIM59 通过抑制环指和含跨膜结构域的蛋白 1 (RNFT1) 诱导的赖氨酸 63 (K63) 泛素化以及随后的 62 kDa (p62) 选择性自噬降解的 Lck SH2 结构域的磷酸酪氨酸独立配体来稳定 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 信号传导的抑制，以控制阿米巴和间质侵袭之间的转变。 PDCD10 过表达或 ROCK 抑制剂的施用可逆转 TRIM59 缺失诱导的收缩表型，从而加速细胞迁移、侵袭和肿瘤形成。这些发现为靶向解除管制的 TRIM59/PDCD10 治疗乳腺癌奠定了基础。对乳腺癌临床样本和小鼠模型的生物信息分析和实验揭示了一种涉及 TRIM59 和 PDCD10 的新信号蛋白降解途径，可调节乳腺癌细胞的生长、存活和转移。癌细胞转移是癌症患者死亡的主要原因。细胞形态的变化对于癌细胞的运动和转移至关重要，这个过程需要对调节细胞极性的信号成分的周转或稳定进行时空控制。自噬是一种高度调控的细胞内降解过程，为癌细胞提供能量来源，同时防止诱变氧化应激以抑制肿瘤发生。但自噬影响细胞转移的机制仍然未知。在这里，我们鉴定了 TRIM59（E3 连接酶家族中的一种蛋白质），已知其靶向泛素化蛋白质进行蛋白酶体或自噬降解，是人类乳腺癌新分子机制的关键组成部分。我们发现 TRIM59 调节 PDCD10 的降解，PDCD10 参与程序性细胞死亡，是驱动毁灭性家族性脑海绵状血管瘤 (CCM) 疾病发病机制的主要因素。我们发现 TRIM59 通过控制 PDCD10 水平来影响细胞形状和收缩性。我们的结果表明，针对 TRIM59-PDCD10 相互作用可能会产生治疗乳腺癌和 CCM 的新治疗策略。
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. Bioinformatic analysis and experiments on clinical samples and mouse models of breast cancer unveil a new signaling protein degradation pathway involving TRIM59 and PDCD10 that modulates breast cancer cell growth, survival, and metastasis. Cancer cell metastasis is the primary cause of mortality in cancer patients. 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. Autophagy—a highly regulated intracellular degradation process—provides cancer cells with access to energy sources while preventing mutagenic oxidative stress to suppress tumorigenesis. But the mechanisms underlying how autophagy impacts cell metastasis remain mostly unknown. Here, we identify TRIM59, a protein in the E3 ligase family known to target ubiquitinated proteins for proteasomal or autophagic degradation, as a key component of a novel molecular mechanism in human breast cancer. 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. We find that TRIM59 has an effect in cell shape and contractility by controlling PDCD10 levels. Our results suggest that targeting the TRIM59-PDCD10 interplay could lead to new therapeutic strategies to treat breast cancer and CCM.
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