UBXN2A enhances CHIP-mediated proteasomal degradation of oncoprotein mortalin-2 in cancer cells.
UBXN2A enhances CHIP-mediated proteasomal degradation of oncoprotein mortalin-2 in cancer cells.
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DOI：
10.1002/1878-0261.12372
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发表时间：
2018-10
影响因子：
6.6
通讯作者：
Rezvani K
中科院分区：
文献类型：
--
作者：
Sane S;Hafner A;Srinivasan R;Masood D;Slunecka JL;Noldner CJ;Hanson AD;Kruisselbrink T;Wang X;Wang Y;Yin J;Rezvani K
癌蛋白的过度表达是目前化疗药物治疗失败的主要原因。药物诱导的癌蛋白降解是可行的，可以改善不同类型癌症的临床结局。Mortalin-2（mot-2）是几种肿瘤中的主要癌蛋白，包括结直肠癌（CRC）。除了使p53肿瘤抑制蛋白失活外，mot-2还增强肿瘤细胞的侵袭和迁移。因此，mot-2被认为是几种癌症类型的潜在治疗靶点。目前的研究调查了一种名为UBXN 2A的泛素样蛋白在调节mot-2周转中的生物学作用。一项正交泛素转移技术，随后进行免疫沉淀、体外泛素化和磁珠TUBE 2下拉实验，结果显示UBXN 2A促进了mot-2的HSP 70相互作用蛋白（CHIP）依赖性泛素化的羧基末端。我们随后发现UBXN 2A增加了mot-2的蛋白酶体降解。亚细胞区室化实验显示，诱导的UBXN 2A降低了mot-2及其伴侣HSP 60的水平。使用小分子藜芦碱（VTD）对UBXN 2A进行药理学上调，降低癌细胞中mot-2的水平。与体外结果一致，UBXN 2A +/−小鼠在结肠组织中表现出mot-2的选择性升高。体外抗K48 TUBE分离方法显示，重组UBXN 2A增强小鼠结肠组织中mot-2的蛋白酶体降解。最后，我们在氧化偶氮甲烷/葡聚糖硫酸钠诱导的小鼠CRC模型中观察到CHIP与肿瘤中UBXN 2A-mot-2复合物的增强缔合。含有UBXN 2A、CHIP和mot-2的多蛋白复合物的存在表明UBXN 2A和CHIP在mot-2富集的肿瘤中具有协同肿瘤抑制活性。这一发现验证了UBXN 2A-CHIP轴作为CRC中新的和潜在的治疗靶点。
Overexpression of oncoproteins is a major cause of treatment failure using current chemotherapeutic drugs. Drug‐induced degradation of oncoproteins is feasible and can improve clinical outcomes in diverse types of cancers. Mortalin‐2 (mot‐2) is a dominant oncoprotein in several tumors, including colorectal cancer (CRC). In addition to inactivating the p53 tumor suppressor protein, mot‐2 enhances tumor cell invasion and migration. Thus, mot‐2 is considered a potential therapeutic target in several cancer types. The current study investigated the biological role of a ubiquitin‐like protein called UBXN2A in the regulation of mot‐2 turnover. An orthogonal ubiquitin transfer technology followed by immunoprecipitation, in vitro ubiquitination, and Magnetic Beads TUBE2 pull‐down experiments revealed that UBXN2A promotes carboxyl terminus of the HSP70‐interacting protein (CHIP)‐dependent ubiquitination of mot‐2. We subsequently showed that UBXN2A increases proteasomal degradation of mot‐2. A subcellular compartmentalization experiment revealed that induced UBXN2A decreases the level of mot‐2 and its chaperone partner, HSP60. Pharmacological upregulation of UBXN2A using a small molecule, veratridine (VTD), decreases the level of mot‐2 in cancer cells. Consistent with the in vitro results, UBXN2A+/− mice exhibited selective elevation of mot‐2 in colon tissues. An in vitro Anti‐K48 TUBE isolation approach showed that recombinant UBXN2A enhances proteasomal degradation of mot‐2 in mouse colon tissues. Finally, we observed enhanced association of CHIP with the UBXN2A‐mot‐2 complex in tumors in an azoxymethane/dextran sulfate sodium‐induced mouse CRC model. The existence of a multiprotein complex containing UBXN2A, CHIP, and mot‐2 suggests a synergistic tumor suppressor activity of UBXN2A and CHIP in mot‐2‐enriched tumors. This finding validates the UBXN2A‐CHIP axis as a novel and potential therapeutic target in CRC.
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