G9a/DNMT1 co-targeting inhibits non-small cell lung cancer growth and reprograms tumor cells to respond to cancer-drugs through SCARA5 and AOX1.

Fecha de publicación: 02/11/2024

Autores de IIS La Fe

Juan Sandoval Del Amor

Autor
Antonio Pineda Lucena

Autor

Participantes ajenos a IIS La Fe

Exposito, Francisco
Redrado, Miriam
Serrano, Diego
Calabuig-Farinas, Silvia
Bao-Caamano, Aida
Gallach, Sandra
Jantus-Lewintre, Eloisa
Diaz-Lagares, Angel
Rodriguez-Casanova, Aitor
San Jose-Eneriz, Edurne
Garcia, Javier
Redin, Esther
Senent, Yaiza
Leon, Sergio
Pio, Ruben
Lopez, Rafael
Oyarzabal, Julen
Agirre, Xabier
Montuenga, Luis M
Prosper, Felipe
Calvo, Alfonso

Grupos

Unidad de Biomarcadores y Medicina de Precisión (UBYMP)

Leader

Agustín Lahoz Rodríguez
Unidad de Descubrimiento de Fármacos (UDF)

Investigador Principal

Leonor Puchades Carrasco

Abstract

The treatment of non-small cell lung cancer (NSCLC) patients has significantly improved with recent therapeutic strategies; however, many patients still do not benefit from them. As a result, new treatment approaches are urgently needed. In this study, we evaluated the antitumor efficacy of co-targeting G9a and DNMT1 enzymes and its potential as a cancer drug sensitizer. We observed co-expression and overexpression of G9a and DNMT1 in NSCLC, which were associated with poor prognosis. Co-targeting G9a/DNMT1 with the drug CM-272 reduced proliferation and induced cell death in a panel of human and murine NSCLC cell lines. Additionally, the transcriptomes of these cells were reprogrammed to become highly responsive to chemotherapy (cisplatin), targeted therapy (trametinib), and epigenetic therapy (vorinostat). In vivo, CM-272 reduced tumor volume in human and murine cell-derived cancer models, and this effect was synergistically enhanced by cisplatin. The expression of SCARA5 and AOX1 was induced by CM-272, and both proteins were found to be essential for the antiproliferative response, as gene silencing decreased cytotoxicity. Furthermore, the expression of SCARA5 and AOX1 was positively correlated with each other and inversely correlated with G9a and DNMT1 expression in NSCLC patients. SCARA5 and AOX1 DNA promoters were hypermethylated in NSCLC, and SCARA5 methylation was identified as an epigenetic biomarker in tumors and liquid biopsies from NSCLC patients. Thus, we demonstrate that co-targeting G9a/DNMT1 is a promising strategy to enhance the efficacy of cancer drugs, and SCARA5 methylation could serve as a non-invasive biomarker to monitor tumor progression.

Datos de la publicación

ISSN/ISSNe:: 2041-4889, 2041-4889
Tipo:: Article
Páginas:: 787-787
DOI:: 10.1038/s41419-024-07156-w
Factor de Impacto:: 2,099 SCImago ℠
Cuartil:: Q1 SCImago ℠

Documentos

No hay documentos

Métricas

Filiaciones

Filiaciones no disponibles

Keywords

GENE-EXPRESSION; PROMOTES

Proyectos asociados

RED TEMATICA DE INVESTIGACION COOPERATIVA EN CANCER (RTICC)

Investigador Principal: MIGUEL ÁNGEL SANZ ALONSO

RD12/0036/0014 . INSTITUTO DE SALUD CARLOS III . 2013

INTEGRATIVE (EPI)GENOMIC AND DRUG TARGET ANALYSIS FOR IDENTIFICATION/VALIDATION OF CLINICALLY VALUABLE BIOMARKERS TO IMPROVE THE POOR OUTCOME OF NON-SMALL CELL LUNG CANCER PATIENTS.

Investigador Principal: JUAN SANDOVAL DEL AMOR

CP13/00055 . INSTITUTO DE SALUD CARLOS III; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2015

UNA APROXIMACIÓN ÓMICA AL DIAGNÓSTICO DE LA TUBERCULOSIS

PCIN-2013-041 . MINISTERIO DE ECONOMIA Y COMPETITIVIDAD; FUNDACIÓN PARA LA INVESTIGACIÓN DEL HOSPITAL UNIVERSITARIO LA FE DE LA COMUNIDAD VALENCIANA . 2015