Journal
MOLECULAR CARCINOGENESIS
Volume -, Issue -, Pages -Publisher
WILEY
DOI: 10.1002/mc.23604
Keywords
histone deacetylase 2; migration and invasion; MTA3; nonsmall cell lung cancer; single-nucleotide polymorphism
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Genome-wide association studies have found an association between HDAC2 rs13213007 and nonsmall cell lung cancer (NSCLC). HDAC2 is upregulated in both peripheral blood mononuclear cells (PBMCs) and NSCLC tissues with the rs13213007 A/A genotype. Clinical data showed a strong association between rs13213007 genotype and N classification. Higher expression of HDAC2 was confirmed to be associated with NSCLC progression. In cell experiments, HDAC2 was found to upregulate c-Myc and cyclin D1 expression, promoting NSCLC cell proliferation, migration, and invasion. MTA3 was also found to interact with HDAC2 and rescue the migration and invasion abilities of NSCLC cells.
Genome-wide association studies have identified numerous single-nucleotide polymorphisms (SNPs) associated with lung cancer; however, the functions of histone deacetylase 2 (HDAC2) rs13213007 and HDAC2 in nonsmall cell lung cancer (NSCLC) remain unclear. Here we identified HDAC2 rs13213007 as a risk SNP and showed that HDAC2 was upregulated in both peripheral blood mononuclear cells (PBMCs) and NSCLC tissues with the rs13213007 A/A genotype compared with those with the rs13213007 G/G or G/A genotype. Patient clinical data indicated strong associations between rs13213007 genotype and N classification. Immunohistochemical staining confirmed that higher expression of HDAC2 was associated with NSCLC progression. Furthermore, we generated 293T cells with the rs13213007 A/A genotype using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 gene editing. Chromatin immunoprecipitation sequencing followed by motif analysis showed that HDAC2 can bind to c-Myc in rs13213007 A/A 293T cells. Cell Counting Kit-8, colony formation, wound-healing, and Transwell assays revealed that HDAC2 upregulates c-Myc and cyclin D1 expression and promotes NSCLC cell proliferation, migration, and invasion. Co-immunoprecipitation, quantitative reverse transcription-polymerase chain reaction, and western blot analysis assays showed that MTA3 interacts with HDAC2, decreases HDAC2 expression, and rescues the migration and invasion abilities of NSCLC cells. Taken together, these findings identify HDAC2 as a potential therapeutic biomarker in NSCLC.
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