Epigenetic Inactivation of α-Internexin Accelerates Microtubule Polymerization in Colorectal Cancer
Epigenetic Inactivation of α-Internexin Accelerates Microtubule Polymerization in Colorectal Cancer
复制标题
α-internexin 的表观遗传失活加速结直肠癌中的微管聚合
DOI：
10.1158/0008-5472.can-20-1590
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发表时间：
2020-12-01
期刊：
影响因子：
11.2
通讯作者：
Luo, Yanxin
中科院分区：
文献类型：
--
作者：
Li, Yingjie;Bai, Liangliang;Luo, Yanxin
DNA甲基化有助于恶性转化，但人们对甲基化如何在早期阶段推动结直肠癌演变知之甚少。在这里，我们通过筛选从全基因组甲基化基因筛选获得的数据，在结肠腺瘤和腺癌中识别异常的INA(α-Interexin)基因甲基化。INA是一种IV型中间丝，其编码基因在启动子区域的CpG岛上经常发生高甲基化。这种高甲基化主要发生在大肿瘤中，是结直肠癌患者总体存活率较低的预后标志。这种表观遗传学改变抑制了腺瘤和腺癌组织中INA的表达。结直肠癌细胞中INA的基因沉默增加了细胞的增殖、迁移和侵袭。恢复INA的表达在体外阻断了细胞的迁移和侵袭，减少了体内的肺转移。从机制上讲，INA在体外直接抑制微管聚合，降低细胞内微管+末端集合率。检测INA中微管蛋白结合位点的多肽阵列筛选发现，位于N-末端头部结构域的微管蛋白结合基序通过与未聚合的微管蛋白结合并阻止微管聚合而发挥肿瘤抑制作用。因此，INA的表观遗传失活是一种中间细丝重组事件，对于促进结直肠癌早期的微管聚合至关重要。意义：这项工作提供了对INA的表观遗传失活的洞察，INA是一种新的已发现的肿瘤抑制因子，它在结直肠癌进展过程中增加微管聚合。
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 (alpha-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 patients with colorectal cancer. 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.Significance: This work provides insight into the epigenetic inactivation of INA, a novel identified tumor suppressor, which increases microtubule polymerization during colorectal cancer progression.