Inflammatory related gene IKKα, IKKβ, IKKγ cooperates to determine liver cancer stem cells progression by altering telomere via heterochromatin protein 1-HOTAIR axis

Cancer stem cells are associated with tumor recurrence. IKK is a protein kinase that is composed of IKK alpha, IKK beta, IKK gamma. Herein, we demonstrate that IKK alpha plus IKK beta promoted and IKK gamma inhibited liver cancer stem cell growth in vitro and in vivo. Mechanistically, IKK alpha plus IKK beta enhanced and IKK gamma inhibited the interplay among HP1 alpha, HP1 beta and HP1 gamma that competes for the interaction among HP1 alpha, SUZ12, HEZ2. Therefore, IKK alpha plus IKK beta inhibited and IKK gamma enhanced the activity of H3K27 methyltransferase SUZ12 and EZH2, which methylates H3K27 immediately sites on HOTAIR promoter region. Therefore, IKK alpha plus IKK beta increased and IKK gamma decreased the HOTAIR expression. Strikingly, IKK alpha plus IKK beta decreases and IKK gamma increases the HP1 alpha interplays with DNA methyltransferase DNMT3b, which increases or decreases TERRA promoter DNA methylation. Thus IKK alpha plus IKK beta reduces and IKK gamma increases to recruit TRF1 and RNA polymerase II deposition and elongation on the TERRA promoter locus, which increases or decreases TERRA expression. Furthermore, IKK alpha plus IKK beta decreases/increases and IKK gamma increases/decreases the interplay between TERT and TRRRA/between TERT and TREC. Ultimately, IKK alpha plus IKK beta increases and IKK gamma decreases the telomerase activity. On the other hand, at the telomere locus, IKK alpha plus IKK beta increases/drcreases and IKK gamma 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 IKK alpha plus IKK beta and IKK gamma to control telomerase activity and telomere length. These observations suggest that HOTAIR operates the action of IKK alpha, IKK beta, IKK gamma in liver cancer stem cells. This study provides a novel basis to elucidate the oncogenic action of IKK alpha, IKK beta, IKK gamma and prompts that IKK alpha, IKK beta, IKK gamma cooperate to HOTAR to be used as a novel therapeutic targets for liver cancer.