Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2
Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2
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DOI：
10.1038/onc.2015.339
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发表时间：
2016-05-19
期刊：
影响因子：
8
通讯作者：
Huang, Y.
中科院分区：
文献类型：
--
作者：
Lucchesi, C.;Sheikh, M. S.;Huang, Y.
食管癌相关基因2（ECRG 2）是一种新的肿瘤抑制基因，其在细胞生长和凋亡调控中的作用尚不清楚。在这里，我们表明，ECRG2的表达上调响应DNA损伤，增加ECRG2表达诱导癌细胞的生长抑制，但不是在非癌性上皮细胞。ECRG2介导的生长抑制与半胱天冬酶的激活和凋亡抑制剂、X染色体连锁凋亡抑制蛋白（XIAP）水平的显著降低相关。ECRG2通过RNA结合蛋白人类抗原R（HuR）调节XIAP mRNA的稳定性和表达。此外，ECRG2增加了HuR的泛素化和降解，但不能调节HuR的非泛素化突变形式。我们还鉴定了各种人类恶性肿瘤中的错义和移码ECRG2突变，并注意到，与野生型ECRG2不同，一种癌症衍生的ECRG2突变体在30位（V30E）含有谷氨酸而不是缬氨酸，未能诱导细胞死亡和半胱天冬酶激活。这种天然存在的V30E突变体也不抑制XIAP和HuR。重要的是，V30E突变体过表达的癌细胞获得了对多种抗癌药物的耐药性，从而表明ECRG2突变似乎在人类恶性肿瘤亚组中获得抗癌药物耐药性方面具有重要作用。
Esophageal cancer-related gene 2 (ECRG2) is a newer tumor suppressor whose function in the regulation of cell growth and apoptosis remains to be elucidated. Here we show that ECRG2 expression was upregulated in response to DNA damage, and increased ECRG2 expression induced growth suppression in cancer cells but not in non-cancerous epithelial cells. ECRG2-mediated growth suppression was associated with activation of caspases and marked reduction in the levels of apoptosis inhibitor, X chromosome-linked inhibitor of apoptosis protein (XIAP). ECRG2, via RNA-binding protein human antigen R (HuR), regulated XIAP mRNA stability and expression. Furthermore, ECRG2 increased HuR ubiquitination and degradation but was unable to modulate the non-ubiquitinable mutant form of HuR. We also identified missense and frame-shift ECRG2 mutations in various human malignancies and noted that, unlike wild-type ECRG2, one cancer-derived ECRG2 mutant harboring glutamic acid instead of valine at position 30 (V30E) failed to induce cell death and activation of caspases. This naturally occurring V30E mutant also did not suppress XIAP and HuR. Importantly, the V30E mutant overexpressing cancer cells acquired resistance against multiple anticancer drugs, thus suggesting that ECRG2 mutations appear to have an important role in the acquisition of anticancer drug resistance in a subset of human malignancies.