SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop.
SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop.
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SENP1 通过 HIF-1α 去SUMOylation 和 SENP1/HIF-1α 正反馈循环促进缺氧诱导的癌症干性
DOI：
10.1136/gutjnl-2016-313264
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发表时间：
2017-12
期刊：
影响因子：
24.5
通讯作者：
Ng IOL
中科院分区：
文献类型：
--
作者：
Cui CP;Wong CC;Kai AK;Ho DW;Lau EY;Tsui YM;Chan LK;Cheung TT;Chok KS;Chan ACY;Lo RC;Lee JM;Lee TK;Ng IOL
目的探讨低氧微环境和低氧诱导因子(HIF)对肝细胞癌(简称肝癌)癌干性的影响及其机制。设计从肝癌细胞的自我更新能力、化疗耐药性、干细胞相关基因的表达和肿瘤干细胞(CSC)标志物阳性细胞群等方面分析肝癌的干细胞特性。用定量聚合酶链式反应检测配对人肝癌细胞中特异性小泛素样修饰物(SUMO)蛋白水解酶1(SENP1)的表达水平。免疫沉淀法检测蛋白质结合情况，染色质免疫沉淀法检测HIFs与缺氧反应元件序列的结合情况。对免疫功能低下的小鼠进行体内鉴定，并分析干细胞频率。结果低氧可增强肝癌细胞的干细胞性和肝癌的发生，其机制可能是通过增强SENP1对HIF-1α的去苏糖化作用，增加HIF-1α的稳定性和转录活性来实现的。此外，我们还证明了SENP1是HIF-1/2α的直接靶标，并且在SENP1和HIF-1α之间存在一个先前未被识别的正反馈环。结论综上所述，我们的研究结果提示，缺氧诱导因子-1α和SENP1之间的正反馈环路在促进肝细胞癌中肿瘤干性增加和低氧条件下的肝癌发生中具有重要意义。针对SENP1的药物可能为肝癌提供一种潜在的新的治疗方法。
Objective We investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness. Design HCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed. Results We showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1α deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1α. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2α and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1α. Conclusions Taken together, our findings suggest the significance of this positive feedback loop between HIF-1α and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.
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