Epigenetic Inactivation of α-Internexin Accelerates Microtubule Polymerization in Colorectal Cancer

Abstract

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 (a-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 tubulinbinding 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.

DNA Methylation in INA, NHLH2, and THBS4 Is Associated with Metastatic Disease in Renal Cell Carcinoma

“…In addition, the hypothetical functional relevance is supported by our finding of the tumor-specific hypermethylation of all three candidates considering that hypermethylation is frequently followed by epigenetic silencing of tumor suppressor genes and subsequent functional changes in RCC [ 15 ]. In line with this, gene silencing by hypermethylation and an association with more invasive tumors was recently reported for INA and THBS4 in other tumor entities [ 36 , 48 ]. Considering our finding of both tumor-specific hypermethylation and an additional increase in the methylation of genes in metastatic tissues, the hypothesis that these epialterations may indicate an increased metastatic potential of cells at an early state of tumor development is supported.…”

“…Moreover, an association of INA hypermethylation with worse histopathological characteristics has been described [ 34 ]. Interestingly, in gastrointestinal neuroendocrine neoplasms and colorectal cancer, INA hypermethylation is associated with a loss of expression, suggesting epigenetic silencing via hypermethylation [ 34 , 36 ].…”

Development and Validation of a Radiosensitivity Prediction Model for Lower Grade Glioma Based on Spike-and-Slab Lasso

“…INA expression on immunohistochemistry in anaplastic gliomas showed a significant positive correlation with 1p/19q codeletion and can replace to some extent 1p/19q (32,33). INA gene methylation is associated with the progression of colon adenoma (34)and gastroenteropancreatic neuroendocrine neoplasms (35). LEPREL1 similarity to the Leprecan family of proteoglycans and as a 3.4 kb transcript encoding an 80 kDa protein (36).…”

DNA methylation-based signature of CD8+ tumor-infiltrating lymphocytes enables evaluation of immune response and prognosis in colorectal cancer

“…Two cohorts with CRC tumor samples from Colon Cancer Family Registry (CCFR) study and Sixth Affiliated Hospital of Sun Yat-sen University (SAH-SYSU) tumor bank were applied in this study. A description of the populations in CCFR study 27 28 and SAH-SYSU samples 29 30 has been published previously. Briefly, the CCFR study cohort included 335 patients with pathologically confirmed CRC at Seattle, Ontario, and Mayo CCFR sites, and the SAH-SYSU cohort consisted of 282 patients with pathologically confirmed CRC at SAH-SYSU from 2008 to 2012.…”