LncRNA GOLGA2P10 is induced by PERK/ATF4/CHOP signaling and protects tumor cells from ER stress-induced apoptosis by regulating Bcl-2 family members
LncRNA GOLGA2P10 is induced by PERK/ATF4/CHOP signaling and protects tumor cells from ER stress-induced apoptosis by regulating Bcl-2 family members
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LncRNA GOLGA2P10 由 PERK/ATF4/CHOP 信号传导诱导，并通过调节 Bcl-2 家族成员来保护肿瘤细胞免受 ER 应激诱导的细胞凋亡
DOI：
10.1038/s41419-020-2469-1
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发表时间：
2020-04-24
影响因子：
9
通讯作者：
Zhuang, Shi-Mei
中科院分区：
文献类型：
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作者：
Wu, Meng-Zhi;Fu, Tao;Zhuang, Shi-Mei
在癌症中经常观察到内质网（ER）应激升高，而持续的ER应激可能引发细胞凋亡。癌细胞如何逃避ER应激诱导的凋亡仍不清楚。在这里，我们发现，假基因衍生的lncRNA，戈尔金A2假基因10（GOLGA 2 P10），经常上调，在肝癌组织中，并显着升高与ER应激诱导剂，如衣霉素和毒胡萝卜素处理的肝癌细胞。GOLGA 2 P10水平越高，HCC患者的无复发生存期越短。在ER应激时，CHOP直接与GOLGA 2 P10的启动子结合，并通过PERK/ATF 4/CHOP途径诱导其转录。有趣的是，ER应激诱导剂刺激的细胞凋亡通过沉默GOLGA 2 P10而促进，但通过过表达GOLGA 2 P10而被拮抗。功能获得和功能丧失分析均揭示GOLGA 2 P10增加BCL-xL蛋白水平，促进BAD磷酸化，并赋予肿瘤细胞对ER应激诱导的凋亡的抗性。此外，BCL-xL过表达或BAD敲低消除了GOLGA 2 P10沉默的促凋亡作用。因此，BAD基因的Ser 75 Ala突变引起的磷酸化抗性进一步增强了BAD对衣霉素诱导的细胞凋亡的促进作用。这些结果表明，ER应激通过PERK/ATF 4/CHOP通路诱导GOLGA 2 P10的转录，并且GOLGA 2 P10的上调通过调节Bcl-2家族成员保护肿瘤细胞免受持续ER应激在肿瘤微环境中的细胞毒性作用，这突出了GOLGA 2 P10作为抗癌治疗的潜在靶点。
Elevated endoplasmic reticulum (ER) stress is frequently observed in cancers, whereas sustained ER stress may trigger apoptosis. How cancer cells escape from ER stress-induced apoptosis remain unclear. Here, we found that a pseudogene-derived lncRNA, Golgin A2 pseudogene 10 (GOLGA2P10), was frequently upregulated in HCC tissues and significantly elevated in hepatoma cells treated with ER stress inducers, such as tunicamycin and thapsigargin. Higher GOLGA2P10 level was correlated with shorter recurrence-free survival of HCC patients. Upon ER stress, CHOP directly bound to the promoter of GOLGA2P10 and induced its transcription via the PERK/ATF4/CHOP pathway. Interestingly, the ER stress inducer-stimulated apoptosis was promoted by silencing GOLGA2P10 but was antagonized by overexpressing GOLGA2P10. Both gain- and loss-of-function analyses disclosed that GOLGA2P10 increased BCL-xL protein level, promoted BAD phosphorylation, and conferred tumor cells with resistance to ER stress-induced apoptosis. Moreover, BCL-xL overexpression or BAD knockdown abrogated the apoptosis-promoting effect of GOLGA2P10 silencing. Consistently, the Ser75Ala mutation in BAD, which caused phosphorylation-resistance, further enhanced the promoting effect of BAD in tunicamycin-induced apoptosis. These results suggest that ER stress induces GOLGA2P10 transcription through the PERK/ATF4/CHOP pathway, and upregulation of GOLGA2P10 protects tumor cells from the cytotoxic effect of persistent ER stress in tumor microenvironment by regulating Bcl-2 family members, which highlight GOLGA2P10 as a potential target for anticancer therapy.