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众所周知，泛素是广泛存在于大多数生物细胞的一种蛋白质，主要功能为标记需要分解的蛋白质，当附有泛素的蛋白质移动到蛋白酶时，蛋白酶就会将该蛋白质分解。2004年，以色列和美国科学家由于发现泛素调节的蛋白质分解过程而共同获得诺贝尔化学奖。泛素调节的蛋白质分解过程包括三个步骤：活化、结合、连接，分别由泛素活化酶E1、泛素结合酶E2、泛素连接酶E3进行催化。泛素连接酶E3具有两个重要的结构区：RING（Really Interesting New Gene：真正有趣的新基因）和HECT（Homologous to the E6-AP Carboxyl Terminu：同源E6相关蛋白质羧基末端）。泛素最终通过两种方式转移至蛋白质：直接从泛素结合酶E2转移至蛋白质（由泛素连接酶E3的RING结构区催化）、通过泛素连接酶E3转移至蛋白质底物（由泛素连接酶E3的HECT结构区催化）。泛素连接酶E3可以维持正常细胞、抑制肿瘤细胞，该酶失调与乳腺癌的发病和进展密切相关，不过具体机制尚不明确。 2019年8月13日，英国《自然》旗下《细胞死亡与分化》在线发表复旦大学上海医学院、复旦大学生物医学研究院、复旦大学附属肿瘤医院李大强、邵志敏等学者的研究报告，发现泛素连接酶E3的RING结构区指状蛋白144A（RNF144A）通过调节热休克蛋白A2（HSPA2）的稳定性和致癌功能，可以对乳腺癌发挥肿瘤抑制作用。 该研究发现，一部分原发乳腺肿瘤与正常乳腺组织相比，RNF144A表达水平显著较低。如果通过DNA甲基化抑制剂恢复RNF144A表达水平，可以抑制乳腺癌细胞的繁殖、集落形成、转移、体外浸润、肿瘤生长、体内肺转移。相反，如果抑制RNF144A表达，可以促进乳腺癌细胞的恶性表型。定量蛋白质组学和生化分析表明，RNF144A可以针对HSPA2发生相互作用，而HSPA2一般被认为是一种癌蛋白，通常高表达于人类癌症，并且促进肿瘤生长和进展，可被泛素化而分解。尤其，RNF144A的连接酶活性缺陷型突变者与其野生型对照者相比，其诱导HSPA2泛素化并分解、抑制乳腺癌细胞繁殖转移浸润的能力发生障碍。此外，通过异位表达HSPA2，可以恢复RNF144A对乳腺癌细胞繁殖、转移、浸润的抑制作用。根据临床，乳腺癌患者RNF144A低表达、HSPA2高表达，与高度恶性临床病理特征存在显著相关性，并且总生存和无病生存显著较差。 因此，该研究结果表明，RNF144A具有抑制乳腺癌生长和转移的重要作用，并且是目前所知首个人类癌症HSPA2泛素连接酶E3靶点，为乳腺癌HSPA2靶向疗法奠定了基础。 相关阅读 Cell Death Differ. 2019 Aug 13. [Epub ahead of print] RNF144A functions as a tumor suppressor in breast cancer through ubiquitin ligase activity-dependent regulation of stability and oncogenic functions of HSPA2. Yin-Long Yang, Ye Zhang, Dou-Dou Li, Fang-Lin Zhang, Hong-Yi Liu, Xiao-Hong Liao, Hong-Yan Xie, Qin Lu, Lin Zhang, Qi Hong, Wen-Jie Dong, Da-Qiang Li, Zhi-Min Shao. Shanghai Cancer Center, Institutes of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China. Deregulation of E3 ubiquitin ligases is intimately implicated in breast cancer pathogenesis and progression, but the underlying mechanisms still remain elusive. Here we report that RING finger protein 144A (RNF144A), a poorly characterized member of the RING-in-between-RING family of E3 ubiquitin ligases, functions as a tumor suppressor in breast cancer. RNF144A was downregulated in a subset of primary breast tumors and restoration of RNF144A suppressed breast cancer cell proliferation, colony formation, migration, invasion in vitro, tumor growth, and lung metastasis in vivo. In contrast, knockdown of RNF144A promoted malignant phenotypes of breast cancer cells. Quantitative proteomics and biochemical analysis revealed that RNF144A interacted with and targeted heat-shock protein family A member 2 (HSPA2), a putative oncoprotein that is frequently upregulated in human cancer and promotes tumor growth and progression, for ubiquitination and degradation. Notably, the ligase activity-defective mutants of RNF144A impaired its ability to induce ubiquitination and degradation of HSPA2, and to suppress breast cancer cell proliferation, migration, and invasion as compared with its wild-type counterpart. Moreover, RNF144A-mediated suppression of breast cancer cell proliferation, migration, and invasion was rescued by ectopic HSPA2 expression. Clinically, low RNF144A and high HSPA2 expression in breast cancer patients was correlated with aggressive clinicopathological characteristics and decreased overall and disease-free survival. Collectively, these findings reveal a previously unappreciated role for RNF144A in suppression of breast cancer growth and metastasis, and identify RNF144A as the first, to our knowledge, E3 ubiquitin ligase for HSPA2 in human cancer. DOI: 10.1038/s41418-019-0400-z
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