Open AccessInflammatory factor receptor Toll‐like receptor 4 controls telomeres through heterochromatin protein 1 isoforms in liver cancer stem cell
Author(s) -
Zheng Qidi,
Xu Jie,
Lin Zhuojia,
Lu Yanan,
Xin Xiaoru,
Li Xiaonan,
Yang Yuxin,
Meng Qiuyu,
Wang Chen,
Xiong Wujun,
Lu Dongdong
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13606
Subject(s) - telomere , telomerase , biology , telomerase reverse transcriptase , microbiology and biotechnology , carcinogenesis , cancer research , rna polymerase ii , gene expression , promoter , gene , genetics
Toll‐like receptor 4 ( TLR 4) 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 TLR 4 promotes the malignant growth of liver cancer stem cells. Mechanistically, TLR 4 promotes the expression of histone‐lysine N‐methyltransferase ( SUV 39 h2) and increases the formation of trimethyl histone H3 lysine 9‐heterochromatin protein 1‐telomere repeat binding factor 2 (H3K9me3‐ HP 1‐ TRF 2) 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 POT 1, pPOT 1, Exo1, pE xo1, SNM 1B and pSNM 1B but prevents binding of CST / AAF to telomere, thus controlling telomere and maintaining telomere length. Furthermore, TLR 4 enhances interaction between HP 1α and DNA methyltransferase ( DNMT 3b), which limits RNA polymerase II deposition on the telomeric repeat‐containing RNA ( TERRA ) promoter region and its elongation, thus inhibiting transcription of TERRA . Ultimately, TLR 4 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 HP 1 isoforms (α, β and γ) are required for the oncogenic action of TLR 4. This study elucidates a novel protection mechanism of TLR 4 in liver cancer stem cells and suggests that TLR 4 can be used as a novel therapeutic target for liver cancer.