PDF(Pubmed)
Abstract：
Lymph node (LN) metastasis is the dominant cause of death in bladder cancer (BCa) patients, but the underlying mechanism remains largely unknown. In recent years, accumulating studies have confirmed that bidirectional mitochondria-nucleus communication is essential for sustaining multiple function of mitochondria. However, little has been studied regarding whether and how the translocation of mitochondrial proteins is involved in LN metastasis. In this study, we first identified that the SUMO E3 ligase MUL1 was significantly downregulated in LN-metastatic BCa tissues and correlated with a good prognosis. Mechanistically, MUL1 SUMOylated HSPA9 at the K612 residue, leading to HSPA9 export from mitochondria and interaction with SUZ12 and in the nucleus. Consequently, MUL1 induced the ubiquitination-mediated degradation of SUZ12 and EZH2 and induced downstream STAT3 pathway inhibition in a HSPA9-dependent manner. Importantly, mutation of HSPA9 SUMO-conjugation motifs limited the translocation of mitochondrial HSPA9 and blocked the HSPA9-SUZ12 and HSPA9-EZH2 interactions. With mutation of the HSPA9 K612 site, the suppressive role of MUL1 overexpression was lost in BCa cells. Further in vitro and in vivo assays revealed that MUL1 inhibits the metastasis and proliferation of BCa cells. Overall, our study reveals a novel function and molecular mechanism of SUMO E3 ligases in LN metastasis.
摘要：
淋巴结（LN）转移是膀胱癌（BCa）患者死亡的主要原因，但是潜在的机制仍然很大程度上未知。近年来,越来越多的研究证实，线粒体-核的双向通讯对于维持线粒体的多种功能至关重要。然而,关于线粒体蛋白的易位是否以及如何参与LN转移的研究很少。在这项研究中,我们首先发现SUMOE3连接酶MUL1在LN转移BCa组织中显著下调,并与良好预后相关.机械上,MUL1在K612残基处的SUMO化HSPA9，导致HSPA9从线粒体输出，并与SUZ12和细胞核相互作用。因此,MUL1诱导泛素化介导的SUZ12和EZH2降解，并以HSPA9依赖性方式诱导下游STAT3途径抑制。重要的是,HSPA9SUMO结合基序的突变限制了线粒体HSPA9的易位，并阻断了HSPA9-SUZ12和HSPA9-EZH2的相互作用。随着HSPA9K612位点的突变，MUL1过表达的抑制作用在BCa细胞中丧失。进一步的体外和体内测定显示MUL1抑制BCa细胞的转移和增殖。总的来说,我们的研究揭示了SUMOE3连接酶在LN转移中的新功能和分子机制。
