LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells
LncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells
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LncRNA HULC 通过稳定 Sirt1 触发自噬并减弱 HCC 细胞的化疗敏感性
DOI：
10.1038/onc.2016.521
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发表时间：
2017-06-22
期刊：
影响因子：
8
通讯作者：
He, F.
中科院分区：
文献类型：
--
作者：
Xiong, H.;Ni, Z.;He, F.
大量证据表明自噬在肿瘤耐药中起重要作用。然而，lncRNA HULC（在肝癌中高度上调）是否参与肝细胞癌（HCC）的自噬和化疗耐药性仍然是未知的。在这项研究中，我们第一次证明，治疗与抗肿瘤药物，如奥沙利铂，5-氟尿嘧啶和吡拉西坦（THP）显着诱导HULC的表达和保护性自噬。HULC沉默通过抑制保护性自噬使HCC细胞对三种抗肿瘤试剂敏感。HULC的异位表达通过稳定沉默信息调节因子1（Sirt 1）蛋白诱导肝癌细胞自噬。对HULC稳定Sirt 1的相应机制的研究表明，HULC上调了泛素特异性肽酶22（USP 22），通过去除Sirt 1上的共轭多聚泛素链，减少了泛素介导的Sirt 1蛋白的降解。此外，我们还发现miR-6825- 5 p、miR-6845- 5 p和miR-6886- 3 p可通过与USP 22 mRNA的3′-非翻译区结合，降低USP 22蛋白的表达。HULC下调了所有三种microRNA（miRNAs），导致USP 22升高。此外，我们发现HULC与Sirt 1蛋白在人肝癌组织中的水平呈正相关。总的来说，我们的数据显示，通路“HULC/USP 22/Sirt 1/保护性自噬”减弱了HCC细胞对化疗药物的敏感性，这表明该通路可能是开发HCC化疗增敏策略的新靶点。
Considerable evidences have shown that autophagy has an important role in tumor chemoresistance. However, it is still unknown whether the lncRNA HULC (highly upregulated in liver cancer) is involved in autophagy and chemoresistance of hepatocellular carcinoma (HCC). In this study, we for the first time demonstrated that treatment with antitumor reagents such as oxaliplatin, 5-fluorouracil and pirarubicin (THP) dramatically induced HULC expression and protective autophagy. Silencing of HULC sensitized HCC cells to the three antitumor reagents via inhibiting protective autophagy. Ectopic expression of HULC elicited the autophagy of HCC cells through stabilizing silent information regulator 1 (Sirt1) protein. The investigation for the corresponding mechanism by which HULC stabilized Sirt1 revealed that HULC upregulated ubiquitin-specific peptidase 22 (USP22), leading to the decrease of ubiquitin-mediated degradation of Sirt1 protein by removing the conjugated polyubiquitin chains from Sirt1. Moreover, we found that miR-6825-5p, miR-6845-5p and miR-6886-3p could decrease the level of USP22 protein by binding to the 3′-untranlated region of USP22 mRNA. All the three microRNAs (miRNAs) were downregulated by HULC, which resulted in the elevation of USP22. In addition, we showed that the level of HULC was positively correlated with that of Sirt1 protein in human HCC tissues. Collectively, our data reveals that the pathway ‘HULC/USP22/Sirt1/protective autophagy’attenuates the sensitivity of HCC cells to chemotherapeutic agents, suggesting that this pathway may be a novel target for developing sensitizing strategy to HCC chemotherapy.