LncAPC 通过 EZH2 介导的 APC 转录抑制驱动 Wnt/β-catenin 激活和肝 TIC 自我更新。

LncAPC drives Wnt/β-catenin activation and liver TIC self-renewal through EZH2 mediated APC transcriptional inhibition.

机构信息

Department of Histology and Embryology, College of Basic Medicine, Zhengzhou University, Henan, China.

Department of Cancer Biology Immunotherapy, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou University, Henan, China.

出版信息

Mol Carcinog. 2018 Mar;57(3):408-418. doi: 10.1002/mc.22764. Epub 2017 Dec 15.

DOI:10.1002/mc.22764

PMID:29144570

Abstract

Liver tumor initiating cells (TICs), a small subset cells in tumor bulk, are responsible for liver tumor initiation, metastasis, and relapse. However, the regulatory mechanism of liver TICs remains largely unknown. Here we found a long noncoding RNA lncAPC, locating near from APC locus, was highly expressed in liver cancer and liver TICs. LncAPC was required for liver TIC self-renewal. Silencing and overexpressing lncAPC showed impaired and enhanced sphere formation capacity of liver TICs, respectively. By recruiting EZH2 to APC promoter, LncAPC inhibits APC transcription and thus drives the activation of Wnt/β-catenin signaling. Attenuate binding between EZH2 and APC promoter was observed upon lncAPC knockdown. What is more, lncAPC-EZH2-APC axis can be targeted to eliminate liver TICs. Altogether, LncAPC promotes liver TIC self-renewal through EZH2-dependent APC transcriptional inhibition.

摘要

肝肿瘤起始细胞（TICs）是肿瘤块中一小部分细胞，负责肝肿瘤的起始、转移和复发。然而，肝 TIC 的调控机制在很大程度上尚不清楚。在这里，我们发现长链非编码 RNA lncAPC 定位于 APC 基因座附近，在肝癌和肝 TICs 中高度表达。lncAPC 是肝 TIC 自我更新所必需的。沉默和过表达 lncAPC 分别显示出肝 TIC 球体形成能力受损和增强。通过招募 EZH2 到 APC 启动子，lncAPC 抑制 APC 的转录，从而驱动 Wnt/β-catenin 信号的激活。在 lncAPC 敲低时观察到 EZH2 与 APC 启动子之间的结合减弱。更重要的是，lncAPC-EZH2-APC 轴可以被靶向以消除肝 TICs。总之，lncAPC 通过 EZH2 依赖性 APC 转录抑制促进肝 TIC 的自我更新。