An Jiahui, Wu Mengying, Xin Xiaoru, Lin Zhuojia, Li Xiaonan, Zheng Qidi, Gui Xin, Li Tianming, Pu Hu, Li Haiyan, Lu Dongdong
School of Life Science and Technology, Tongji University, Shanghai 200092, China.
Oncotarget. 2016 Aug 2;7(31):50131-50149. doi: 10.18632/oncotarget.10321.
Cancer stem cells are associated with tumor recurrence. IKK is a protein kinase that is composed of IKKα, IKKβ, IKKγ. Herein, we demonstrate that IKKα plus IKKβ promoted and IKKγ inhibited liver cancer stem cell growth in vitro and in vivo. Mechanistically, IKKα plus IKKβ enhanced and IKKγ inhibited the interplay among HP1α, HP1β and HP1γ that competes for the interaction among HP1α, SUZ12, HEZ2. Therefore, IKKα plus IKKβ inhibited and IKKγ enhanced the activity of H3K27 methyltransferase SUZ12 and EZH2, which methylates H3K27 immediately sites on HOTAIR promoter region. Therefore, IKKα plus IKKβ increased and IKKγ decreased the HOTAIR expression. Strikingly, IKKα plus IKKβ decreases and IKKγ increases the HP1α interplays with DNA methyltransferase DNMT3b, which increases or decreases TERRA promoter DNA methylation. Thus IKKα plus IKKβ reduces and IKKγ increases to recruit TRF1 and RNA polymerase II deposition and elongation on the TERRA promoter locus, which increases or decreases TERRA expression. Furthermore, IKKα plus IKKβ decreases/increases and IKKγ increases/decreases the interplay between TERT and TRRRA/between TERT and TREC. Ultimately, IKKα plus IKKβ increases and IKKγ decreases the telomerase activity. On the other hand, at the telomere locus, IKKα plus IKKβ increases/drcreases and IKKγ decreases/increases TRF2, POT1, pPOT1, Exo1, pExo1, SNM1B, pSNM1B/CST-AAF binding, which keep active telomere regulatory genes and poised for telomere length. Strikingly, HOTAIR is required for IKKα plus IKKβ and IKKγ to control telomerase activity and telomere length. These observations suggest that HOTAIR operates the action of IKKα, IKKβ, IKKγ in liver cancer stem cells. This study provides a novel basis to elucidate the oncogenic action of IKKα, IKKβ, IKKγ and prompts that IKKα, IKKβ, IKKγ cooperate to HOTAR to be used as a novel therapeutic targets for liver cancer.
癌症干细胞与肿瘤复发相关。IKK是一种蛋白激酶，由IKKα、IKKβ、IKKγ组成。在此，我们证明IKKα加IKKβ促进而IKKγ抑制肝癌干细胞在体外和体内的生长。机制上，IKKα加IKKβ增强而IKKγ抑制HP1α、HP1β和HP1γ之间的相互作用，它们竞争HP1α、SUZ12、HEZ2之间的相互作用。因此，IKKα加IKKβ抑制而IKKγ增强H3K27甲基转移酶SUZ12和EZH2的活性，其使HOTAIR启动子区域上的H3K27位点甲基化。因此，IKKα加IKKβ增加而IKKγ降低HOTAIR的表达。引人注目的是，IKKα加IKKβ减少而IKKγ增加HP1α与DNA甲基转移酶DNMT3b的相互作用，这增加或减少TERRA启动子DNA甲基化。因此，IKKα加IKKβ减少而IKKγ增加在TERRA启动子位点招募TRF1和RNA聚合酶II的沉积和延伸，这增加或减少TERRA的表达。此外，IKKα加IKKβ减少/增加而IKKγ增加/减少TERT与TRRRA之间/TERT与TREC之间的相互作用。最终，IKKα加IKKβ增加而IKKγ降低端粒酶活性。另一方面，在端粒位点，IKKα加IKKβ增加/减少而IKKγ减少/增加TRF2、POT1、pPOT1、Exo1、pExo1、SNM1B、pSNM1B/CST - AAF的结合，这保持端粒调控基因活跃并维持端粒长度。引人注目的是，HOTAIR是IKKα加IKKβ和IKKγ控制端粒酶活性和端粒长度所必需的。这些观察结果表明HOTAIR在肝癌干细胞中发挥IKKα、IKKβ、IKKγ的作用。本研究为阐明IKKα、IKKβ、IKKγ的致癌作用提供了新的基础，并提示IKKα、IKKβ、IKKγ与HOTAR协同作用可作为肝癌的新型治疗靶点。
