Journal
CANCER RESEARCH
Volume 80, Issue 23, Pages 5203-5215Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-1590
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Funding
- National Basic Research Program of China (973 Program) [2015CB554001]
- National Natural Science Foundation of China [81972245, 31900505, 81902877]
- Natural Science Fund for Distinguished Young Scholars of Guangdong Province [2016A030306002]
- Five Five Talent Team Construction Project of the Sixth Affiliated Hospital of Sun Yat-sen University [P20150227202010244, P20150227202010251]
- Sun Yat-sen University Clinical Research 5010 Program [2018026]
- Natural Science Foundation of Guangdong Province [2018A030313567, 2016A030310222, 2018A0303130303]
- Program of Introducing Talents of Discipline to Universities
- National Key Clinical Discipline (2012)
- China Postdoctoral Science Foundation [2018M633241]
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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.
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