Institute of Basic Medical Sciences, 27 Taiping Road, Beijing 100850, China.
Beijing Institute of Brain Sciences, 27 Taiping Road, Beijing 100850, China.
Theranostics. 2019 Jan 24;9(3):811-828. doi: 10.7150/thno.29271. eCollection 2019.
Targeting cancer stem cells (CSCs) has been proposed as a new strategy to eradicate malignancies, including hepatocellular carcinoma (HCC). However, the mechanisms by which CSCs sustain their self-renewal and chemoresistance remain elusive. Nanog is a master transcriptional regulator of stemness, especially in CSCs. Its expression is tightly regulated by the ubiquitin-proteasome system in embryonic stem cells (ESCs). Whether the suppression of Nanog ubiquitination contributes to its over-expression in CSCs has not been explored. In addition, the role of receptor for activated C kinase 1 (RACK1), an adaptor protein implicated in HCC growth, in liver CSC-like traits remains to be determined. : and assays were performed to investigate the role of RACK1 in liver CSC-like phenotype and murine ESC function. How RACK1 regulates Nanog expression was explored by immunoblotting and immunohistochemistry. The interaction of RACK1 with Nanog and the consequent effects on Nanog ubiquitination and stemness were then analyzed. : RACK1 promotes self-renewal and chemoresistance of human liver CSCs and maintains murine ESC function. Consistently, RACK1 enhances the expression of Nanog in human HCC cells and murine ESCs. The protein levels of RACK1 in clinical HCC tissues positively correlate with those of Nanog. Further exploration indicates that RACK1 directly binds to Nanog, which prevents its recruitment of E3 ubiquitin ligase FBXW8 and ubiquitin-dependent degradation. The interaction with Nanog is essential for RACK1 to promote stemness. : Our data provide novel insights into the regulation of Nanog protein levels, as well the key role of RACK1 to enhance self-renewal and chemoresistance of CSCs in human HCC.
靶向肿瘤干细胞（CSCs）已被提议作为一种新策略来根除恶性肿瘤，包括肝细胞癌（HCC）。然而，CSCs 维持自我更新和化疗耐药的机制仍不清楚。Nanog 是干性的主要转录调节因子，尤其是在 CSCs 中。它的表达在胚胎干细胞（ESCs）中受到泛素-蛋白酶体系统的严格调节。Nanog 泛素化的抑制是否有助于其在 CSCs 中的过度表达尚未得到探索。此外，受体激活蛋白激酶 C1（RACK1）在 HCC 生长中的作用，作为一种衔接蛋白，在肝 CSC 样特征中的作用仍有待确定。我们通过和实验来研究 RACK1 在肝 CSC 样表型和鼠 ESC 功能中的作用。通过免疫印迹和免疫组化来探讨 RACK1 调节 Nanog 表达的作用。然后分析了 RACK1 与 Nanog 的相互作用及其对 Nanog 泛素化和干性的影响。结果表明，RACK1 促进了人肝 CSCs 的自我更新和化疗耐药，并维持了鼠 ESC 的功能。一致地，RACK1 增强了人 HCC 细胞和鼠 ESC 中 Nanog 的表达。临床 HCC 组织中 RACK1 的蛋白水平与 Nanog 的蛋白水平呈正相关。进一步的探索表明，RACK1 直接与 Nanog 结合，阻止其招募 E3 泛素连接酶 FBXW8 和泛素依赖性降解。与 Nanog 的相互作用对于 RACK1 促进干性是必不可少的。我们的数据为 Nanog 蛋白水平的调节提供了新的见解，以及 RACK1 在增强人 HCC 中 CSCs 的自我更新和化疗耐药中的关键作用。
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