Overexpression of MEOX2 and TWIST1 Is Associated with H3K27me3 Levels and Determines Lung Cancer Chemoresistance and Prognosis

Abstract

Lung cancer is the leading cause of death from malignant diseases worldwide, with the non-small cell (NSCLC) subtype accounting for the majority of cases. NSCLC is characterized by frequent genomic imbalances and copy number variations (CNVs), but the epigenetic aberrations that are associated with clinical prognosis and therapeutic failure remain not completely identify. In the present study, a total of 55 lung cancer patients were included and we conducted genomic and genetic expression analyses, immunohistochemical protein detection, DNA methylation and chromatin immunoprecipitation assays to obtain genetic and epigenetic profiles associated to prognosis and chemoresponse of NSCLC patients. Finally, siRNA transfection-mediated genetic silencing and cisplatinum cellular cytotoxicity assays in NSCLC cell lines A-427 and INER-37 were assessed to describe chemoresistance mechanisms involved. Our results identified high frequencies of CNVs (66–51% of cases) in the 7p22.3–p21.1 and 7p15.3–p15.2 cytogenetic regions. However, overexpression of genes, such as MEOX2, HDAC9, TWIST1 and AhR, at 7p21.2–p21.1 locus occurred despite the absence of CNVs and little changes in DNA methylation. In contrast, the promoter sequences of MEOX2 and TWIST1 displayed significantly lower/decrease in the repressive histone mark H3K27me3 and increased in the active histone mark H3K4me3 levels. Finally these results correlate with poor survival in NSCLC patients and cellular chemoresistance to oncologic drugs in NSCLC cell lines in a MEOX2 and TWIST1 overexpression dependent-manner. In conclusion, we report for the first time that MEOX2 participates in chemoresistance irrespective of high CNV, but it is significantly dependent upon H3K27me3 enrichment probably associated with aggressiveness and chemotherapy failure in NSCLC patients, however additional clinical studies must be performed to confirm our findings as new probable clinical markers in NSCLC patients.

MicroRNA-122-3p inhibits tumor cell proliferation and induces apoptosis by targeting Forkhead box O in A549 cells

“…The prevalence and mortality rates of lung cancer have increased worldwide (1)(2)(3). The detection and pathological research of lung cancer are important in the diagnosis and therapy of cancer diseases (4,5).…”

“…The results revealed that overexpression of miR-122-3p suppressed lung cancer cell proliferation. Subsequently, 5-bromo-2-deoxyuridine (BrdU) staining assay 3 cells/well) were seeded onto a 96-well plate and cultured with 400 µl antibiotic-free DMEM. Then, the mixture was added to the cell culture plates and incubated at 37˚C in 5% CO 2 .…”

Mechanism and molecular network of RBM8A-mediated regulation of oxaliplatin resistance in hepatocellular carcinoma via EMT

“…It is worth noting that HDAC9 is a TF that is closely related to the RBM8A-mediated regulation of OXA resistance in HCC. Abnormally high HDAC9 expression has been shown to be closely related to malignant biological behaviors such as proliferation, invasion and metastasis in various tumors [41][42][43][44][45]. In recent years, a variety of HDAC inhibitors have been widely used in basic research and clinical anticancer treatment [46,47], representing a current research hotspot.…”

Epigenetics in non-small cell lung carcinomas

“…51 This findings suggest the importance of the three main epigenetic mechanisms, DNA methylation, histone code modifications and chromatin remodeling complexes in cancer progression (table I and II). [52][53][54][55][56][57][58] Along with, overexpression of BRG1 and BRM in the cisplatin toxicity, 50 or doxorubicin chemo resistance mechanisms associated with the expression of the subunits SMARCB1 and SMARCA4 (BRG1) in front to NSCLC cells. 51 All of that, suggesting the importance of the three main epigenetic mechanisms DNA methylation, histone code modifications and chromatin remodeling complexes in cancer progression and potential new oncological therapeutic strategies in NSCLC, all of which have been shown in…”

“…21 In particular, Van Den Broeck and colleagues in 2008, have identified that trimethylation state in lysine 20 of histone H4 (H4K20me3) allows the prognosis stratification of AD-NSCLC patients with higher risk of death in clinical stage I. H4K20me3 has additionally been proposed as biomarker in subgroups of AD patients with poor differential clinical prognosis, and potentially determinant for the use of adjuvant chemotherapy. 71 Additionally, while low levels of the histone mark H3K27me3 have been associated with chemo resistance and poor prognosis in NSCLC patients, 56 additional reports have confirmed that higher expression of H3K27me3 correlates with better overall survival (OS) and better prognosis, redefining subgroups of NSCLC patients with an epigenetic phenotype and different clinical outcome. 72 Additionally, despite histone marks H3K4me2, H2AK5ac and H3K9ac are related to global and diseasefree survival in early clinical stages of NSCLC patients, undergoing curative surgical resection.…”