Epigenetic Inactivation of α-Internexin Accelerates Microtubule Polymerization in Colorectal Cancer.
结直肠癌
癌症
组蛋白
生物
癌细胞
作者
Yingjie Li,Liangliang Bai,Huichuan Yu,Du Cai,Xiaolin Wang,Baoyuan Huang,Shaoyong Peng,Meijin Huang,Guangwen Cao,Andrew M. Kaz,William M. Grady,Jianping Wang,Yanxin Luo
出处
期刊:Cancer Research [American Association for Cancer Research] 日期:2020-12-01卷期号:80 (23): 5203-5215被引量:4
标识
DOI:10.1158/0008-5472.can-20-1590
摘要
DNA methylation contributes to malignant transformation, but little is known about how the methylation drives colorectal cancer evolution at the early stages. Here we identify aberrant INA (α-internexin) gene methylation in colon adenoma and adenocarcinoma by filtering data obtained from a genome-wide screen of methylated genes. The gene encoding INA, a type IV intermediate filament, was frequently hypermethylated in CpG islands located in the promoter region. This hypermethylation preferentially occurred in large tumors and was a prognostic marker for poor overall survival in colorectal cancer patients. This type of epigenetic alteration silenced INA expression in both adenoma and adenocarcinoma tissues. Gene silencing of INA in colorectal cancer cells increased cell proliferation, migration, and invasion. Restored INA expression blocked migration and invasion in vitro and reduced lung metastasis in vivo. Mechanistically, INA directly inhibited microtubule polymerization in vitro and decreased intracellular microtubule plus-end assembly rates. A peptide array screen surveying the tubulin-binding sites in INA identified a tubulin-binding motif located in the N-terminal head domain that plays a tumor-suppressive role by binding to unpolymerized tubulins and impeding microtubule polymerization. Thus, epigenetic inactivation of INA is an intermediate filament reorganization event that is essential to accelerate microtubule polymerization in the early stages of colorectal cancer.