title: 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.
authors.affiliation: Universidad Nacional Autónoma de México (UNAM), Facultad de Estudios Superiores (FES)-Iztacala, Biomedicine Research Unit (UBIMED), Cancer Epigenomics Laboratory 12, Tlalnepantla, Mexico State, Mexico; Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: Federico
authors.initials: F
authors.lastname: Ávila-Moreno
authors.affiliation: Universidad Nacional Autónoma de México (UNAM), Facultad de Estudios Superiores (FES)-Iztacala, Biomedicine Research Unit (UBIMED), Cancer Epigenomics Laboratory 12, Tlalnepantla, Mexico State, Mexico.
authors.forename: Leonel
authors.initials: L
authors.lastname: Armas-López
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: Aldo M
authors.initials: AM
authors.lastname: Álvarez-Moran
authors.affiliation: Universidad Nacional Autónoma de México (UNAM), Facultad de Estudios Superiores (FES)-Iztacala, Biomedicine Research Unit (UBIMED), Cancer Epigenomics Laboratory 12, Tlalnepantla, Mexico State, Mexico; Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico; Johns Hopkins University, Medical Institutions, Maryland, Baltimore, United States of America.
authors.forename: Zoila
authors.initials: Z
authors.lastname: López-Bujanda
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: Blanca
authors.initials: B
authors.lastname: Ortiz-Quintero
authors.affiliation: Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Hidalgo-Miranda
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: Francisco
authors.initials: F
authors.lastname: Urrea-Ramírez
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: R María
authors.initials: RM
authors.lastname: Rivera-Rosales
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Vázquez-Manríquez
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: Erika
authors.initials: E
authors.lastname: Peña-Mirabal
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: José
authors.initials: J
authors.lastname: Morales-Gómez
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Vázquez-Minero
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: José L
authors.initials: JL
authors.lastname: Téllez-Becerra
authors.affiliation: Universidad Nacional Autónoma de México (UNAM), Facultad de Estudios Superiores (FES)-Iztacala, Biomedicine Research Unit (UBIMED), Cancer Epigenomics Laboratory 12, Tlalnepantla, Mexico State, Mexico.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ramírez-Mendoza
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Ávalos-Bracho
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: Enrique Guzmán
authors.initials: EG
authors.lastname: de Alba
authors.affiliation: Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico.
authors.forename: Karla
authors.initials: K
authors.lastname: Vázquez-Santillán
authors.affiliation: Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico.
authors.forename: Vilma
authors.initials: V
authors.lastname: Maldonado-Lagunas
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: Patricio
authors.initials: P
authors.lastname: Santillán-Doherty
authors.affiliation: Unidad de Investigación Médica en Enfermedades Oncológicas (UIMEO), Instituto Mexicano del Seguro Social (IMSS), Centro Médico Nacional (CMN), Siglo XXI, México City, México.
authors.forename: Patricia
authors.initials: P
authors.lastname: Piña-Sánchez
authors.affiliation: Instituto Nacional de Enfermedades Respiratorias (INER), Mexico City, Mexico.
authors.forename: Joaquin
authors.initials: J
authors.lastname: Zúñiga-Ramos
mesh_terms: D000328:Adult; D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002869:Chromosome Aberrations; D002897:Chromosomes, Human, Pair 7; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006657:Histones / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D051879:Twist-Related Protein 1 / Q000235:genetics*
chemical_list: D006657:Histones; D018398:Homeodomain Proteins; C484193:MEOX2 protein, human; D009687:Nuclear Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1