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

Qidi Zheng,Jie Xu,Yanan Lu,Yuxin Yang,Qiuyu Meng,Xiaonan Li,Wujun Xiong,Chen Wang,Dongdong Lu,Xiaoru Xin,Zhuojia Lin

doi:10.1111/jcmm.13606

Qidi Zheng, Jie Xu + Show 9 more

Open Access

https://doi.org/10.1111/jcmm.13606

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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.

Highlights

Toll-like receptor (TLR) family plays a fundamental role in pathogen recognition and activation of innate immunity
Of particular importance is Toll-like receptor 4 (TLR4)-mediated recruitment of endothelial progenitors derived from immature myeloid cells[1]; especially, TLR4 plays a crucial role in mesenchymal stem cell (MSC)induced inhibition of natural killer (NK) cell function.[2]
Given that TLR4 enhances the interplay between heterochromatin protein 1 (HP1) isoforms (HP1a, HP1b and HP1c), increases the telomere length by HP1H3K9me[3] and increases telomerase activity by HP1-DNMT3b pathway, we studied whether HP1 (HP1a, HP1b and HP1c) could determine the TLR4 oncogenic function

Summary

| INTRODUCTION

Toll-like receptor (TLR) family plays a fundamental role in pathogen recognition and activation of innate immunity. Of particular importance is TLR4-mediated recruitment of endothelial progenitors derived from immature myeloid cells[1]; especially, TLR4 plays a crucial role in mesenchymal stem cell (MSC)induced inhibition of natural killer (NK) cell function.[2] excessive TLR4 expression is accompanied by chromatin. We investigated whether TLR4 promotes the malignant proliferation and growth of liver cancer stem cells in vitro and in vivo, and investigated its potential role in the malignant transformation of liver stem cells by analysing the cascade of TLR4-HP1 (a, b and c)-telomere signalling

| MATERIALS AND METHODS

| RESULTS

Findings

| DISCUSSION