Inflammatory factor receptor Toll‐like receptor 4 controls telomeres through heterochromatin protein 1 isoforms in liver cancer stem cell

Abstract

Toll‐like receptor 4 (TLR4) which acts as a receptor for lipopolysaccharide (LPS) has been reported to be involved in carcinogenesis. However, the regulatory mechanism of it has not been elucidated. Herein, we demonstrate that TLR4 promotes the malignant growth of liver cancer stem cells. Mechanistically, TLR4 promotes the expression of histone‐lysine N‐methyltransferase (SUV39 h2) and increases the formation of trimethyl histone H3 lysine 9‐heterochromatin protein 1‐telomere repeat binding factor 2 (H3K9me3‐HP1‐TRF2) complex at the telomeric locus under mediation by long non coding RNA urothelial cancer‐associated 1 (CUDR). At the telomeric locus, this complex promotes binding of POT1, pPOT1, Exo1, pExo1, SNM1B and pSNM1B but prevents binding of CST/AAF to telomere, thus controlling telomere and maintaining telomere length. Furthermore, TLR4 enhances interaction between HP1α and DNA methyltransferase (DNMT3b), which limits RNA polymerase II deposition on the telomeric repeat‐containing RNA (TERRA) promoter region and its elongation, thus inhibiting transcription of TERRA. Ultimately, TLR4 enhances the telomerase activity by reducing the interplay between telomerase reverse transcriptase catalytic subunit (TERT) and TERRA. More importantly, our results reveal that tri‐complexes of HP1 isoforms (α, β and γ) are required for the oncogenic action of TLR4. This study elucidates a novel protection mechanism of TLR4 in liver cancer stem cells and suggests that TLR4 can be used as a novel therapeutic target for liver cancer.

The Role of Toll-Like Receptors in Oncotherapy

“…The activation of TLR4 also induces production of immunosuppressive agents and chemokines, which increase tumor progression and metastasis, including nitric oxide, IL-8, and MMP-9. Additionally, silencing TLR4 in the context of liver cancer has the potential to decrease tumor cell metastasis 16 .…”

miR24‐2 accelerates progression of liver cancer cells by activating Pim1 through tri‐methylation of Histone H3 on the ninth lysine

“…Cells were transiently transfected with luciferase construct plasmids with the use of the Lipofectamine TM 2000 (Invitrogen). After incubation for 36‐48 hours, the cells were harvested with Passive Lysis Buffer (Promega), and luciferase activities of cell extracts were measured with the use of the dual‐luciferase assay system (Promega) according to the manufacturer's instructions and our pervious protocol …”

The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells

“…Histone methylation is a known epigenetic mechanism that induces transcriptional repression via chromatin modification. In human liver CSCs, transcription of the lncRNA CUDR was stimulated by TLR4, which promoted their proliferation in vitro and growth in vivo, via control of histone methylation and telomere elongation [ 146 ]. TLR4 action also prompted a stable interaction between CUDR, SUV39 h2, and histone 3, which led to epigenetic repression in liver CSCs [ 146 ].…”

“…In human liver CSCs, transcription of the lncRNA CUDR was stimulated by TLR4, which promoted their proliferation in vitro and growth in vivo, via control of histone methylation and telomere elongation [ 146 ]. TLR4 action also prompted a stable interaction between CUDR, SUV39 h2, and histone 3, which led to epigenetic repression in liver CSCs [ 146 ]. This function, mediated by this lncRNA, controlled downstream pathways, including telomere length, playing a fundamental role in controlling CSC survival [ 146 ] ( Figure 3 ).…”

“…TLR4 action also prompted a stable interaction between CUDR, SUV39 h2, and histone 3, which led to epigenetic repression in liver CSCs [ 146 ]. This function, mediated by this lncRNA, controlled downstream pathways, including telomere length, playing a fundamental role in controlling CSC survival [ 146 ] ( Figure 3 ).…”